CN101830889B - Pyrimidine derivatives - Google Patents
Pyrimidine derivatives Download PDFInfo
- Publication number
- CN101830889B CN101830889B CN2010101974578A CN201010197457A CN101830889B CN 101830889 B CN101830889 B CN 101830889B CN 2010101974578 A CN2010101974578 A CN 2010101974578A CN 201010197457 A CN201010197457 A CN 201010197457A CN 101830889 B CN101830889 B CN 101830889B
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- formula
- alkoxyl group
- hydroxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 0 COc1cc(Nc2nccc(N(*)c3cc(*)c(*)c(*)c3*)n2)cc(OC)c1OC Chemical compound COc1cc(Nc2nccc(N(*)c3cc(*)c(*)c(*)c3*)n2)cc(OC)c1OC 0.000 description 1
- TUFWXJQIXKPQDB-UHFFFAOYSA-N NS(c1ccccc1Nc1ccnc(Nc2ccc(cn[nH]3)c3c2)n1)(=O)=O Chemical compound NS(c1ccccc1Nc1ccnc(Nc2ccc(cn[nH]3)c3c2)n1)(=O)=O TUFWXJQIXKPQDB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/08—Antiseborrheics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
There are provided compounds of formula (I), wherein X, R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8> and R<9> are as indicated in claim 1, useful in disorders where ZAP-70 and/or Syk inhibition plays a role or caused by a malfunction of signal cascades connected with FAK.
Description
The application is dividing an application of Chinese patent application 03806101.5, and the applying date of original application is on March 14th, 2003, and denomination of invention is " pyrimidine derivatives ".
The present invention relates to pyrimidine derivatives, relate to they production method, they are as the purposes of medicine, and relate to the pharmaceutical composition that comprises them.
More specifically, the present invention provides the formula I compound of free form or salt form in first aspect,
Wherein, X is=CR
0-or=N-;
R
0, R
1, R
2, R
3And R
4In each be hydrogen independently; Hydroxyl; C
1-C
8Alkyl; C
2-C
8Alkenyl; C
3-C
8Alkyl; C
3-C
8Cycloalkyl-C
1-C
8Alkyl; Hydroxyl C
1-C
8Alkyl; C
1-C
8Alkoxy C
1-C
8Alkyl; Hydroxyl C
1-C
8Alkoxy C
1-C
8Alkyl; Randomly can be by hydroxyl, C on ring
1-C
8Alkoxyl group, carboxyl or C
1-C
8The aryl C that alkoxy carbonyl replaces
1-C
8Alkyl;
Or R
3And R
4Reach the nitrogen and the carbon atom that connect with their and form 5 to 10 yuan of heterocycles, and comprise extraly 1,2 or 3 heteroatoms that is selected from N, O and S;
Or R
1, R
2And R
3In each be halogen, halo-C independently
1-C
8Alkyl; C
1-C
8Alkoxyl group, halo-C
1-C
8Alkoxyl group, hydroxyl C
1-C
8Alkoxyl group; C
1-C
8Alkoxy C
1-C
8Alkoxyl group; Aryl; Aryl C
1-C
8Alkoxyl group; Heteroaryl; Heteroaryl-C
1-C
4Alkyl; 5 to 10 yuan of heterocycles; Nitro; Carboxyl; C
2-C
8Alkoxy carbonyl; C
2-C
8Alkyl-carbonyl;-N (C
1-C
8Alkyl) C (O) C
1-C
8Alkyl;-N (R
10) R
11-CON (R
10) R
11-SO
2N (R
10) R
11Or-C
1-C
4-alkylidene group-SO
2N (R
10) R
11R wherein
10And R
11In each be hydrogen independently; Hydroxyl; C
1-C
8Alkyl; C
2-C
8Alkenyl; C
3-C
8Cycloalkyl; C
3-C
8Cycloalkyl-C
1-C
8Alkyl; C
1-C
8Alkoxy C
1-C
8Alkyl; Hydroxyl C
1-C
8Alkoxy C
1-C
8Alkyl; Hydroxyl C
1-C
8Alkyl; (C
1-C
8Alkyl)-carbonyl; Randomly can be by hydroxyl, C on ring
1-C
8Alkoxyl group, carboxyl or C
2-C
8The aryl C that alkoxy carbonyl replaces
1-C
8Alkyl; Or 5 to 10 yuan of heterocycles;
Or R
1And R
2Form aryl or comprise heteroatomic 5 to 10 yuan of heteroaryls that one or two is selected from N, O and S with the C-atom that connects with them; Or
R
5And R
6In each be hydrogen independently; Halogen; Cyano group; C
1-C
8Alkyl; Halo-C
1-C
8Alkyl; C
2-C
8Alkenyl; C
2-C
8Alkynyl; C
3-C
8Cycloalkyl; C
3-C
8Cycloalkyl C
1-C
8Alkyl; C
5-C
10Aryl C
1-C
8Alkyl;
R
7, R
8And R
9In each be hydrogen independently; Hydroxyl; C
1-C
8Alkyl; C
2-C
8Alkenyl; Halo-C
1-C
8Alkyl; C
1-C
8Alkoxyl group; C
3-C
8Cycloalkyl; C
3-C
8Cycloalkyl C
1-C
8Alkyl; Aryl C
1-C
8Alkyl;
-Y-R
12, wherein Y is direct key or an O, and R
12Be a replacement or unsubstitutedly comprise 1,2 or 3 heteroatomic 5,6 or 7 yuan of heterocycle that are selected from N, O and S; Carboxyl, (C
1-C
8Alkoxyl group)-carbonyl;-N (C
1-8Alkyl)-CO-NR
10R
11-CONR
10R
11-N (R
10) (R
11);-SO
2N (R
10) R
11R
7And R
8Or R
8And R
9, form with the carbon atom that connects with their respectively and comprise 1,2 or 3 the heteroatomic 5 or 6 yuan of heteroaryl that is selected from N, O and S; Or 5 or 6 yuan of carbocyclic rings.
Any aryl can be phenyl, naphthyl or 1,2,3,4-tetralin base, preferred phenyl.Heteroaryl is heteroaromatic, and such as 5 or 6 membered aromatic heterocycles, it randomly is condensed on 1 or 2 phenyl ring and/or other heterocycle.
Any heterocycle can be saturated or unsaturated, and randomly is condensed on 1 or 2 phenyl ring and/or other heterocycle.
The example of heterocycle or heteroaryl comprises for example morpholinyl, piperazinyl, piperidyl, pyrrolidyl, pyridyl, purine radicals, pyrimidyl, N-methyl-azepine-suberane-4-base, indyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydric quinoline group, benzothiazolyl, thiazolyl, imidazolyl, benzimidazolyl-, Ben Bing oxadiazolyl, benzotriazole base, 2,3-indanyl, oxadiazolyl, pyrazolyl, triazolyl and tetrazyl.Preferred heterocycle or heteroaryl are morpholinyl, piperazinyl, piperidyl, pyrrolidyl, pyridyl, N-methyl-azepine-suberane-4-base, thiazolyl, imidazolyl and tetrazyl.
Work as R
7And R
8Or R
8And R
9When forming together 5 or 6 yuan of carbocyclic rings with connected carbon atom, this ring can be preferably cyclopentyl or cyclohexyl.
Halo-alkyl alkyl that to be wherein one or more H replaced by halogen is (such as CF
3).
Any alkyl or moieties can be straight or brancheds.C
1-8Alkyl is C preferably
1-4Alkyl.C
1-8Alkoxyl group is C preferably
1-4Alkoxyl group.Any alkyl, alkoxyl group, alkenyl, cycloalkyl, heterocycle, aryl or heteroaryl can not be substituted (unless otherwise mentioned) or by one or more halogens that are selected from; OH; C
1-C
8Alkyl; C
1-C
8Alkoxyl group; Nitro; Cyano group; COOH; Formamyl; C (NH
2)=NOH;-N (R
10) R
11C
3-C
6Cycloalkyl; 3 to 7 yuan of heterocycles; Phenyl; Phenyl-C
1-4Alkyl; The substituting group of 5 or 6 yuan of heteroaryls replaces.When alkyl, alkoxyl group or alkenyl were substituted, its substituting group was preferably located on the terminal C atom.When heterocycle or assorted aromatic nucleus are substituted (as top disclosed), replacement can be on one or more ring carbon atoms and/or theheterocyclic nitrogen atom (if existence).Substituent example on the theheterocyclic nitrogen atom is, for example C
1-8Alkyl, formamyl ,-C (NH
2)=NOH ,-NR
10R
11, C
3-6Cycloalkyl or phenyl-C
1-4Alkyl, preferably C
1-8Alkyl, C
3-6Cycloalkyl or phenyl-C
1-4Alkyl.
The alkyl that preferably replaces or alkoxyl group are (such as R
7) be that its terminal C atom is by OH, C
1-4The alkyl of alkoxyl group or heterocyclic substituted or alkoxyl group.Work as R
10Or R
11When being 5 to 10 yuan of heterocycles, it can be thiazolyl for example.
Halogen can be F, Cl, Br or I.
Preferably, R at the most
1, R
2Or R
3One of them is CONR
10R
11Or SO
2NR
10R
11, more preferably be SO
2NR
10R
11
The compounds of this invention can exist with the form of free form or salt, for example with as the additive salt that forms of organic or mineral acid (for example trifluoroacetic acid or spirit of salt), or when they comprise carboxylic group, for example by and alkali (for example alkali-metal salt, such as sodium, potassium or replacement or non-substituted ammonium salt) react and obtainable salt.
In formula I, independently, jointly or in any combination or the subgroup mode of closing preferably have following meaning:
(a) X is=CR
0
(b) R
0Hydrogen; Halogen (such as Cl); C
1-C
4Alkyl (such as methyl or ethyl); C
1-4Alkyl (such as methoxyl group); Preferred hydrogen;
(c) R
1Hydrogen, halogen (such as Cl or F); OH; C
1-C
8Alkyl (such as methyl or ethyl); The C that replaces
1-8Alkyl is (such as the C of terminal OH replacement
1-8Alkyl);-SO
2N (R
10) R
11-N (C
1-4Alkyl) C (O) C
1-4Alkyl; The N atom randomly is substituted 5 or 6 yuan of heterocycles of (when possibility) on the ring; C
1-C
8Alkoxyl group (such as methoxyl group); Aryl (such as phenyl); Or and R
2And and R
1And R
2The C-atom that connects forms 5 to 10 yuan of aryl or heteroaryls together, and the latter comprises 1 or 2 nitrogen-atoms;
(d) R
2Hydrogen; Hydroxyl, C
1-C
8Alkyl (such as methyl or ethyl); The C that replaces
1-8Alkyl is (such as terminal OH-or C
1-4The C that-alkoxyl group replaces
1-8Alkyl); C
1-8Alkoxyl group; C
1-C
4Alkoxy C
1-C
8Alkoxyl group;-CON (R
10) R
11-SO
2N (R
10) R
11Or and R
1And R
1And R
2The C-atom that connects forms 5 to 10 yuan of aryl or heteroaryls together, and the latter comprises 1 or 2 nitrogen-atoms;
(e) R
3Hydrogen; Halogen (such as Cl, Br); Hydroxyl; C
1-C
8Alkyl (such as methyl or ethyl); The C that replaces
1-C
8Alkyl is (such as the C of terminal OH replacement
1-8Alkyl); Carboxyl; CONR
10R
11-SO
2N (R
10) R
11Theheterocyclic nitrogen atom (when possibility) is substituted 5 or 6 yuan of heterocycles randomly; Or and R
4And and R
3And R
4The N and the C atom that connect form 6 yuan of heterocycles together.
(f) R
4Hydrogen; Or and R
3And and R
3And R
4The N and the C atom that connect form 6 yuan of heterocycles together; Preferred hydrogen;
(g) R
5Hydrogen; Halogen; C
1-4Alkyl; Or CF
3
(h) R
6Hydrogen
(i) R
7Hydrogen; Hydroxyl; C
1-4Alkyl; The C that replaces
1-4Alkyl is (such as the C of terminal OH replacement
1-4Alkyl); C
1-8Alkoxyl group; The C that replaces
1-8Alkoxyl group is (such as end by OH, C
1-4Alkoxyl group or heterocyclic substituted); NR
10R
11-SO
2N (R
10) R
11-Y-R
12CF
3Or R
7And R
8And and R
7And R
8The C-atom that links to each other form together 5 yuan of heterocycles (as by-NH-CH=CH-,-CH=CH-NH-,-NH-N=CH-,-CH=N-NH-,-NH-N=N-or-the N=N-NH-bridge joint);
(k) R
8Hydrogen; Hydroxyl; C
1-4Alkoxyl group; Carboxyl; 5 or 6 yuan of heterocycles that ring C or N atom are randomly replaced; N (C
1-4Alkyl)-CO-NR
10R
11Or and R
7Or R
9And and R
7And R
8Or R
8And R
9The C-atom that links to each other respectively form together 5 yuan of heteroaryls (as by-NH-CH=CH-,-CH=CH-NH-,-NH-N=CH-,-CH=N-NH-,-NH-N=N-or-the N=N-NH-bridge joint);
(1) R
9Hydrogen; C
1-4Alkoxyl group; NR
10R
11Or and R
8And and R
8And R
9The C atom that links to each other form together 5 yuan of heteroaryls (as by-NH-CH=CH-,-CH=CH-NH-,-NH-N=CH-,-CH=N-NH-,-NH-N=N-or-the N=N-NH-bridge joint);
(m) R
10And R
11One of them is hydrogen or C independently
1-4Alkyl, another one are hydrogen; OH; C
1-8The C of alkyl, replacement
1-8Alkyl is (such as end by OH, C
3-6Cycloalkyl or heterocyclic substituted); C
2-8Alkenyl; C
3-8Cycloalkyl; Hydroxyl C
1-8Alkoxy C
1-8Alkyl; Or 5 yuan of heterocycles.
R
3SO preferably
2NR
10R
11
The present invention also is provided for the method for production I compound, and this method comprises the compound with formula II
R wherein
1, R
2, R
3, R
4, R
5, R
6With X be as defined above, Y is leavings group, preferred halogen, for example
Bromine, iodine, or chlorine particularly
React with the formula III compound
R wherein
7, R
8And R
9Such as top definition,
Then reclaim the free form obtain or the formula I compound of salt form, and as required, will be converted into the salt form of wanting with the formula I compound that free form obtains, vice versa.
This method can be implemented according to means known in the art, for example describes among the embodiment 1 to 4.
Formula II compound as initial substance can pass through formula IV compound
Obtain with the reaction of formula V compound:
R wherein
1, R
2, R
3, R
4, R
5, R
6, Y and X be as defined above.
Formula IV and V compound are known or can be according to currently known methods productions.
The following example is illustrated the present invention and is not consisted of any limitation of the invention.
Following abbreviation is used: the APC=allophycocyanin, BINAP=2,2 '-two (diphenylphosphino)-1,1 '-binaphthylyl, cDNA=complementary DNA, the DCM=methylene dichloride, the DIAD=diisopropyl azo-2-carboxylic acid, DMAP=4-Dimethylamino pyridine, DMF=dimethyl formamide, the DMSO=methyl-sulphoxide, the DMF=dimethyl formamide; Pmc=2,2,5,7,8-pentamethyl-benzo dihydropyrane; The tBu=tertiary butyl; DIPCDI=N, N '-DIC; DTT=1,4-two sulphur-D, L-threitol; The DNA=thymus nucleic acid, the EDTA=ethylenediamine tetraacetic acid (EDTA), Lck=lymph sample T-cell protein tyrosine kinase, LAT-11=is used for the adaptor proteins of T cell activation, RT=room temperature; The RT-PCR=reverse transcriptional PCR, the molion that the MS=electrospray ionization mass spectrum is measured is (such as M+H
1+), the Eu=europium; The ZAP-70=ζ chain 70kD albumen of being correlated with; The Syk=p72syk protein tyrosine kinase; The SA=streptavidin.
(1H-indazole-6-base is amino)-pyrimidine-4-yl is amino for embodiment 1:2-[2-]-benzsulfamide
(a) 2-(2-chloro-pyrimidine-4-yl is amino)-benzsulfamide: with 22.1g (148.42mmol, 3 equivalents) 2,4-dichloro pyrimidine and 200ml10M hydrochloric acid (200mmol, 4 equivalents) add to 8.52g (49.47mmol) 2-aminobenzene sulfonamide in the suspension of 200ml Virahol.Suspension stirred 2 hours 15 minutes in 60 ℃.With 2 liters of ethyl acetate diluted reaction mixtures, add 500ml water.By adding sodium bicarbonate pH is adjusted to 8-9.Again aqueous layer extracted of 500ml ethyl acetate is used in layering subsequently.Use the dried over sodium sulfate organic layer, filter, then be evaporated to the 300ml volume.Crystal settling forms and removes (by product) by filtering.Filtrate is evaporated to 100ml, and the product crystallization produces 2-(2-chloro-pyrimidine-4-yl is amino)-benzsulfamide (reaching 97% purity by HPLC) thus.Be further purified the mother liquor of this crystallization by column chromatography, crystallization produces more 2-(2-chloro-pyrimidine-4-yl is amino)-benzsulfamide.
(b) 2-[2-(1H-indazole-6 base is amino)-pyrimidine-4-yl amino]-benzsulfamide: with the dense HCl of 13ml
*(130mmol, 5 equivalents) add to 7.25g (25.46mmol) 2-(2-chloro-pyrimidine-4-yl is amino)-benzsulfamide and 4.07g (30.55mmol, the 1.2 equivalents) suspension of 6-Aminoindazole in the 400ml Virahol.Backflow suspension 4 hours 30 minutes.With 1.5 liters of ethyl acetate diluted reaction mixtures, add 1 premium on currency.By adding sodium bicarbonate pH is adjusted to 8-9.Again aqueous layer extracted of 500ml ethyl acetate is used in layering.Use the dried over sodium sulfate organic layer, filter, then be evaporated to the 300ml volume.Crystal settling (1.01g) forms and removes (by product) by filtering.The chromatography purification filtrate of 200g silica gel with ethyl acetate/methanol 95/5v/v wash-out.Form crystallization after the evaporation and filter and produce title compound.
1H NMR(400MHz，DMSO-d
6)：δ9.42(s，1H)，8.34(d，1h)，8.28(d，1H)，8.27(s，1H)，7.93(s，1H，7.88(d，1H)，7.62(m，2H)，7.32(d，1H)，7.24(t，1H)，6.40(d，1H)。
MSm/z(％)：382(M+H，100)；
Embodiment 2:2-[2-(3,4,5-trimethoxy-phenyl amino)-pyrimidine-4-yl is amino]-benzsulfamide
Except replacing outside the 6-Aminoindazole with 3,4,5-trimethoxy-phenyl amine in step (b), prepare title compound by embodiment 1 description from 2-(2-chloro-pyrimidine-4-yl is amino)-benzsulfamide.
1H NMR(400MHz，DMSO-d
6)：δ9.18(s，1H)，8.22(d，1H)，8.17(d，1H)，7.89(d，1H)，7.55(t，1H)，7.25(t，1H)，7.14(s，2H)，6.40(d，1H)，3.69(s，6H)，3.62(s，3H).MSm/z(％)：432(M+H，100)；
Embodiment 3:2-methyl-6-[2-(3,4,5-trimethoxy-phenyl amino)-pyrimidine-4-yl is amino]-benzsulfamide
Except in step (a), using 2-amino-6-methyl-benzsulfamide to replace the 2-aminobenzene sulfonamide, press embodiment 1 and describe the preparation title compound.
According to Girard, the people such as Y; J.J.Chem.Soc.Perkin Trans.I 1979,4,1043-10472 describes and can prepare 2-amino-6-methyl-benzsulfamide: under the nitrogen environment-and during 55-49 ℃, with meta-aminotoluene (32.1g, 32.5ml, 0.30mmol) be added dropwise in nitroethane (400ml) solution of Sulfuryl chloride isocyanate (51.3ml, 83.6g, 0.59mmol).Remove cryostat, mixture is warming up to-8 ℃ and adds subsequently aluminum chloride (51g, 0.38mmol).Heated mixt to 100 ℃ 20 minutes forms the clarification brown solution, it is cooled to room temperature then is poured on ice.After filtering, washing with frozen water and diethyl ether, collecting precipitation is dissolved in dioxane (300ml) with it.Add entry (1000ml) and dense HCl (1500ml) and form suspension, be heated to 120 ℃ 18 hours.Wash this clarification brown solution with diethyl ether/hexane (1400ml, 1/1v/v) after being cooled to RT, make pH=8 by adding the yellow soda ash adjustment.With ethyl acetate (2x1000ml) extraction, water (500ml) and salt solution (500ml) washing organic phase, drying (using sal epsom), then the concentrated brown solid that produces uses this brown solid of chromatography purification of methylene dichloride/ethanol (100/1v/v) wash-out to produce the target product of white solid at silicon-dioxide.
Fusing point: 72-75 ℃ (Virahol);
1H NMR (400MHz, DMSO-d
6): δ 2.64 (s, 3H, Me), 3.63 (s, 3H, OMe), 3.68 (s, 6H, OMe), 6.31 (d, J=5Hz, 1H, pyrimidine CH), 7.07 (d, J=8Hz, 1H, aromatics CH), 7.15 (s, 2H, aromatics CH), 7.40 (t, J=8Hz, 1H, aromatics CH), 7.65 (s, 2H, SO
2NH
2), 8.04 (d, J=8Hz, 1H, aromatics CH), 8.12 (d, J=5Hz, 1H, pyrimidine CH), 9.14 (s, 1H, NH), 9.40 (s, 1H, NH).
MS(ES
+)m/z：446(MH
+)，468(MNa
+)
MS(ES
-)：444(M-H)
-
Embodiment 4:2-methoxyl group-6-[2-(3,4,5-trimethoxy-phenyl amino)-pyrimidine-4-yl is amino]-benzsulfamide
Except in step (a), using 2-amino-6-methoxyl group-benzsulfamide to replace 2-amino-6-methyl-benzsulfamide, can prepare title compound according to embodiment 1 description.
Can prepare 2-amino-6-methoxyl group-benzsulfamide from the meta-anisidine of 12.3g according to the similar approach with embodiment 1a description.
NMR (400MHz, DMSO-d
6): δ 3.62 (s, 3H, OMe), 3.69 (s, 6H, OMe), 3.91 (s, 3H, OMe), 6.31 (d, J=5Hz, 1H, pyrimidine CH), 6.86 (d, J=8Hz, 1H, aromatics CH), 7.12 (s, 2H, aromatics CH), (7.43 t, J=8Hz, 1H, aromatics CH), 8.01 (d, J=8Hz, 1H, aromatics CH), 8.11 (d, J=5Hz, 1H, pyrimidine CH), (9.18 s, 1H, NH), 9.79 (br, 1H, NH).
MS(ES
+)：462.2(MH
+)，484.2(MNa
+)
MS(ES
-)：460.3(M-H)
-
Formula X
1Compound,
R wherein
3, R
7And R
8Such as table 1 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 1
Formula X
2Compound,
R wherein
3And R
8Such as table 2 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 2
Formula X
3Compound,
R wherein
1, R
7, R
8And R
9Such as table 3 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 3
| Implement | R 1 | R 7 | R 8 | R 9 | The MS data |
| Example | ＊ES+ | ＊ES- | ||||
| 61 | -SO 2NH-CH 2CH 2- O-CH 2CH 2-OH | -H | -N(CH 3)- C(O)CH 3 | -H | ||
| 62 | -SO 2NH 2 | -OCH 3 | -OCH 3 | -OCH 3 | ||
| 63 | -SO 2NH 2 | -O-CH 2CH 2-1-imidazolyl | -OCH 3 | -H | ||
| 64 | -SO 2NH-CH 2CH 2- O-CH 2CH 2-OH | -OCH 3 | -OCH 3 | -OCH 3 | 520 | 518 |
| 65 | -N(CH 3)C(O)CH 3 | -OCH 3 | -OCH 3 | -OCH 3 | 424 | 422 |
| 66 | -CH 2CH 2-OH | -SO 2NH-CH 2CH 2CH 2 CH 3 | -H | -H | ||
| 67 | -SO 2NH 2 | -OCH 3 | -H | -OCH 3 | ||
| 68 | -SO 2NH 2 | -O-CH 2CH 2-1-imidazolyl | -H | -H | ||
| 69 | -CH 2CH 2-OH | -O-CH 2CH 2-1-imidazolyl | -H | -H | ||
| 70 | -CH 2CH 2-OH | -OCH 3 | -H | -OCH 3 | ||
| 71 | -SO 2NH 2 | -OH | -H | -H | ||
| 72 | -O-CH 2CH 2-OH | -O-CH 2CH 2-1-imidazolyl | -H | -H | ||
| 73 | -SO 2The NH-2-thiazolyl | -OCH 3 | -OCH 3 | -OCH 3 | 515 | 513 |
Formula X
4Compound,
R wherein
2, R
5, R
7, R
8And R
9Such as table 4 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 4
Formula X
5Compound,
R wherein
0, R
1, R
2, R
3And R
4Such as table 5 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 5
Formula X
6Compound,
R wherein
5, R
7, R
8And R
9Such as table 6 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 6
Formula X
7Compound,
R wherein
1, R
2, R
3, R
7And R
8Such as table 7 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 7
Formula X
8Compound,
R wherein
1, R
2, R
3And R
8Such as table 8 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 8
Formula X
9Compound,
R wherein
7, R
8And R
9Such as table 9 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 9
| Embodiment | R 7 | R 8 | R 9 | ＊ES+ | ＊ES- |
| 173 | -O-CH 2CH 2-piperidino | -OCH 3 | -H | 470.3 | 468.3 |
| 174 | -O-(1-methyl-nitrogen heterocyclic heptan-4-yl) | -H | -H | 440 | |
| 175 | -O-(1-methyl-nitrogen heterocyclic penta-2-yl) | -H | -H | 440 | 438 |
| 176 | -O-CH 2CH 2-CH 2-1-imidazolyl | -OCH 3 | -H | 467 | 465 |
| 177 | -OCH 3 | -OCH 3 | -OC H 3 | ||
| 178 | -O-CH 2CH 2-1-(1,2,4-triazolyl) | -H | -H | 424 | 422 |
| 179 | -O-CH 2CH 2-piperidino | -H | -H | ||
| 180 | -O-CH 2CH 2-OH | -OCH 3 | -H | ||
| 181 | -O-CH 2CH 2-4-morpholino | -H | -H | 442 | 440 |
| 182 | -O-CH 2CH 2CH 2-1-imidazolyl | -H | -H |
Formula X
10Compound,
R wherein
1, R
7And R
9Such as table 10 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 10
| Embodiment | R 1 | R 7 | R 9 | ＊ES+ | ＊ES- |
| 183 | -CH 2CH 2-OH | -OCH 3 | -OCH 3 | 411 | 409 |
| 184 | -SO 2NH 2 | -O-CH 2CH 2-1-imidazolyl | -H | 496.3 | 494.3 |
Formula X
11Compound,
R wherein
8Be-OCH
3(embodiment 185) or-OH (embodiment 186), can be by preparing according to the method for embodiment 1 with suitable initiator.
Formula X
12Compound,
R wherein
0, R
1, R
7, R
8And R
9Such as table 12 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 12
Formula X
13Compound,
R wherein
1, R
2, R
3And R
5Such as table 13 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 13
| Embodiment | R 1 | R 2 | R 3 | R 5 | ＊ES+ | ＊ES- |
| 208 | -H | -H | -SO 2NHCH 3 | -CF 3 | 514.0 | |
| 209 | -H | -H | -SO 2NHC 3H 7 | -Br | ||
| 210 | -H | -H | -SO 2NH-CH 2The CH-cyclopropyl | -Br | ||
| 211 | -H | -H | -SO 2NHCH 3 | -CH 3 | ||
| 212 | -H | -H | -SO 2N(CH 3) 2 | -Br | ||
| 213 | -H | -H | -SO 2NHCH 3 | -Cl | ||
| 214 | -H | -H | -SO 2NHCH 3 | -I | ||
| 215 | -H | -H | -SO 2NHCH 3 | -Br | ||
| 216 | -CH 3 | -OCH 3 | -SO 2NH 2 | -H | 476 | 474 |
| 217 | -H | Piperidino-(1-position only) | -SO 2NH 2 | -H | 515.5 | 513.4 |
| 218 | -H | Morpholino | -SO 2NH 2 | -H | 517.4 | 515.4 |
| 219 | -H | -C 2H 5 | -SO 2NH 2 | -H | ||
| 220 | -H | -CH 3 | -SO 2NH 2 | -Cl | ||
| 221 | -H | -CH 3 | -SO 2NHCH 3 | -H | 460.4 | |
| 222 | -H | Phenyl | -SO 2NH 2 | -H | 508.2 | 506.3 |
Formula X
14Compound,
R wherein
2, R
3, R
5, R
7, R
8And R
9Such as table 14 definition, can be by preparing with the method for suitable initiator according to embodiment 1.
Table 14
ES+ refers to electrospray MS positive ion mode; ES-refers to electrospray MS negative ion mode; And EL refers to electronic impact MS
Formula I compound and their pharmacologically acceptable salt demonstrate valuable pharmaceutical properties in external test, so useful as drug.
The compounds of this invention shows that ZAP-70 (ζ chain-associated protein of 70KD), focal adhesion kinase (FAK) and/or Syk protein tyrosine kinase suppress active especially.More particularly, compound of the present invention has activity to people ZAP-70, FAK and/or Syk protein tyrosine kinase.Interaction between the compounds of this invention and ZAP-70, FAK and/or Syk protein tyrosine kinase can by their stop people ZAP-70 protein tyrosine kinase phosphorylation for example LAT-11 (SEQ ID NO:1), stop for example Biot-Y397 (SEQ ID NO:2) of human FAK protein tyrosine kinase phosphorylation, and/or stop in the aqueous solution for example for example polyglutamic acid-tyrosine (Glu of people Syk protein tyrosine kinase phosphorylation, Tyr) ability demonstration, this point for example shows according to following experimental technique.
1. acellular kinase assay: ZAP-70 and Syk kinase assay
ZAP-70, Lck and Syk be at Upstate Biotechnology, Lake Placid, and NY has commercially available.
The preparation of LAT-11 (SEQ ID NO:1): be used as the peptide LAT-11 of substrate in the ZAP-70 kinase assay, can prepare as disclosed among the embodiment 1A of WO 02/12275, its content is particularly quoted as a reference about embodiment 1A herein.
The ZAP-70 kinase assay: the activity of reagent of the present invention is measured in the homogeneous phase ZAP-70 kinase assay of time-based resolution FRET (fluorescence resonance energy transfer).In brief, 80nM ZAP-70 and 80nM Lck and 4 μ M ATP are at ZAP-70 kinase buffer liquid (20mM Tris, pH 7.5,10 μ MNa
3VO
4, 1mM DTT, 1 mM MnCl
2, 0.01% bovine serum albumin 0.05%Tween20) was hatched 1 hour under the room temperature in silication polypropylene test tube.Then, bringing Selection In property LCK inhibitor PP2 (4-amino-5-(4-chloro-phenyl)-7-(tertiary butyl) pyrazoles [3,4-d] pyrimidine; AlexisBiochemicals) (final concentration is 1.2 μ M) hatched 10 minutes again.10 these solution of μ l and 10 μ l were hatched under the room temperature 4 hours as the biotinylation peptide LAT-11 (1 μ M) of substrate and the inhibitor mixed of 20 μ l serial dilutions.Kinase reaction is detecting termination in the damping fluid (0.05%Tween 20 for 20mM Tris, pH 7.5,0.01% bovine serum albumins) with 10 μ l 10mMEDTA solution.The antiphosphotyrosine antibody of detecting stage by in detecting damping fluid, adding 50 μ l europium (Eu) marks (Eu-PT66 for example; Final concentration 0.125nM; Advant/Wallac) and 50 μ l streptavidin-allophycocyanin (SA-APC; Final concentration 40nM) carries out.Incubated at room after 1 hour as on Victor2 multiple labeling counter (Wallac) in 665nm place detection fluorescence.Background value (low contrast) obtains in without laboratory sample and ATP situation and deducts from whole values.At the signal that does not have to obtain under the test sample condition as 100% (high contrast).The restraining effect that will obtain when test compound is arranged is calculated as the percent inhibition of high contrast.Cause 50% restraining effect (IC
50) test compound concentration determined by dose-response curve.In this assay method, the compounds of this invention IC
50The scope of value is from 10nM to 2 μ M, preferably from 10nM to 100nM.The compound exhibits IC of embodiment 4
50Value 12nM.
The Syk kinase assay: the activity of reagent of the present invention is measured in the heterogeneous Syk kinase assay based on group of the lanthanides fluoroimmunoassay (DELFIA) technology of dissociating-strengthening.This method detects by what Syk carried out with the antiphosphotyrosine antibody of europium chelating mark and phosphoric acid is transferred to the polyglutamic acid-tyrosine (Glu that is coated on the microtiter plate, Tyr) substrate, such as (Braunwalder AF, Yarwood DR, Sills MA, Lipson KE, the time-resolved fluorescence method of use europium sequestrant is measured the protein tyrosine kinase activity of C-Src, Anal.Biochem.1996; 238 (2): 159-64) describe.Then with time-resolved dissociating-the strengthen amount of fluorescent quantitation phosphorylation.In brief, with poly (Glu, the Tyr) (4:1 of 100 μ l; 2 μ g/ml are coated to elisa plate in phosphate buffered saline buffer PBS, ambient temperature overnight.Remove poly (Glu, Tyr) solution, add the PBS that 250 μ l contain 1% bovine serum albumin, placed 1 hour under the room temperature.Then use 350 μ l lavation buffer solutions (25mM Tris-HCl, pH 7.4, contain 0.03%Tween-20) to wash plate three times.By with the serial dilutions of 30 μ l inhibitor and 30 μ l Syk kinases (20g/ml) and ATP (1 μ M) at kinase buffer liquid (20mM Tris, pH 7.5,10 μ MNa
3VO
4, 1mM DTT, 10mM MnCl
2, 2mM MgCl
2, 0.01% bovine serum albumin, 0.05%Tween 20) the middle mixing, kinase reaction at room temperature carried out 1 hour.After washing as mentioned above plate four times, add resisting-phosphotyrosine antibody PY20 (Advant/Wallac) (100ng/ml in 50mM Tris-HCl of 60 μ l DELFIA europium N1-marks, pH7.4,150mMNaCl, 20 μ M Titriplex V, 0.2% bovine serum albumin 0.05%Tween-20) was also at room temperature hatched 1 hour.After washing plate eight times, add 60 μ l and strengthen solution (Wallac).Measure fluorescence (Victor2 at the 615nm place; Wallac).High control value (100% signal) obtains under the test sample condition not having, and low control value (background) obtains under test sample and the ATP condition not having.From whole values, deduct low control value.The restraining effect that obtains when having test compound is calculated as the percent inhibition to the height contrast.Cause 50% inhibiting test compound concentration (IC
50) determine from dose-response curve.In this assay method, the compounds of this invention has from 100nM to 10 μ M, preferably the IC from 100nM to 1 μ M
50The value scope.The compound of embodiment 128 has IC
50The value tool is 150nM.
2. allotype mixed lymphocyte reacion (MLR)
The compounds of this invention demonstrates the T cell inhibitory activity.More particularly, the compounds of this invention stops activation and/or the propagation of T cell in the aqueous solution for example, for example as according to shown in the following experimental technique.According to standard method (J.Immunol.Methods, 1973,2,279 and the people such as Meo T., Immunological Methods, New York, Academic Press, 1979,227-39) carry out two-way MLR.In brief, (105 cells of every kind of mouse 1.6x place each hole of flat tissue culture microtiter plate, amount to 3.2x 10 from the splenocyte of CBA and BALB/c mouse
5) containing 10%FCS, 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates (Gibco BRL, Basel, Switzerland), 50 μ M 2 mercapto ethanol (Fluka, Buchs, Switzerland), hatch in the RPMI substratum of serial dilution compound.Each test compound carries out 73 times of dilution step, and each dilution is carried out 2 times.After hatching 4 days, add 1 μ Ci
3The H-thymus pyrimidine.Collecting cell behind the other 5 hours incubation periods mixes according to standard method mensuration
3The H-thymus pyrimidine.The background value of MLR (low contrast) is independent BALB/c cell proliferation.From all values, deduct low contrast.Height contrast without any sample is bred as 100%.The inhibition percentage that calculation sample causes, and measure 50% restraining effect (IC
50Value) required concentration.In this assay method, the compounds of this invention has from 10nM to 10 μ M IC
50The value scope is preferably from 10nM to 100nM.The compound exhibits IC of embodiment 120
50Value is 13nM.
3.FAK assay method
All black microtiter plate carries out in the 96-hole in steps in institute.The human FAK kinase domain of the restructuring 6-histidine mark of purifying is diluted to the concentration of 94ng/mL (2.5nM) with dilution buffer liquid (50mM HEPES, pH 7.5,0.01%BSA, 0.05%Tween-20 is in water).By with 10 μ L5x kinase buffer liquid (250mM HEPES, pH7.5,50 μ M Na
3VO
4, 5mM DTT, 10mM MgCl
2, 50mM MnCl
2, 0.05%BSA, 0.25%Tween-20 the aqueous solution), 20 μ L water, the aqueous solution of 5 μ L, 4 μ M biotinylation peptide substrates (Biot-Y397), 5 μ L test compounds in DMSO mix with 5 μ L recombinase solution, and came the preparation feedback mixture in 30 minutes in incubated at room.Begin enzyme reaction by adding 5 μ L, the 5 μ M ATP aqueous solution, mixture was hatched 3 hours at 37 ℃.Add 200 μ L and detect mixture (1nM Eu-PT66 in dilution buffer liquid, 2.5 μ g/mL SA-(SL) APC, 6.25mM EDTA) termination reaction, after hatching 30 minutes under the room temperature, the FRET signal from the europium to the allophycocyanin is measured by ARVOsx+L (Perkin Elmer).The color cancellation effect that the ratio of 665nm and the fluorescence intensity of 615nm causes with the Elimination test compound with the FRET signal that acts on data analysis.The result measures with the inhibition percentage of enzymic activity.DMSO and 0.5M EDTA suppress contrast as 0% and 100% respectively.IC
50Value uses the curve fitting analysis for nonlinearity of OriginPro6.1 program (OriginLab) to determine.In this assay method, the compound of formula I suppresses the IC of FAK activity
50＜1 μ M.Embodiment 188,208 and 213 shows respectively IC
50Value is 15nM, 1nM and 7nM.
Biot-Y397 peptide (Biotin-SETDDYAEIID ammonium salt, SEQ ID NO:2) is designed to have same acid sequence to the D402 zone and prepare with standard method from S392 with people GeneBank accession number L13616.
The human FAK kinase domain of the restructuring 6-histidine mark of purifying obtains by the following method: by using 5, PCR primer (ATGGCAGCTGCTTACCTTGAC, SEQ ID NO:3) and 3 ' PCR primer (TCAGTGTGGTCTCGTCTGCCC, SEQ ID NO:4) from people's placenta Marathon-Ready
TMCDNA (Clontech, No.7411-1) carries out pcr amplification, separate the human FAK cDNA of total length, and subclone enters pGEM-T carrier (Promega, No.A3600).After AccIII digestion, the dna fragmentation of purifying is processed with the Klenow fragment.The cDNA fragment is with BamHI digestion and be cloned into the pFastBacHTb plasmid (Invitrogen Japan K.K., Tokyo) that cuts with BamHI and Stu I in advance.The plasmid hFAKKD (M384-G706) that obtains/pFastBacHTb is checked order to confirm its structure.364 amino acid whose protein of the dna encoding that obtains, this albumen contains the 6-histidine mark, and an intersegmental septal area and one are at the rTEV proteolytic enzyme cutting site of N-end and from 29 to 351 FAK kinase domain (Met384-Gly706).
Use MaxEfficacy DH10Bac intestinal bacteria (E.coli) cell, the donor plasmid swivel base is advanced the Baculovirus Gene group.By at Bac-to-
The simple alkaline lysis of describing in the baculovirus expression system (Invitrogen) prepares Bacmid DNA.Based on the supplier (
Invitrogen) method that provides, transfection Sf 9 insect cell.The expression of FAK is carried out the Western engram analysis by SDS-PAGE with Anti-Human FAK monoclonal antibody (clone #77 is from TransductionLaboratories) in each lysate.
The virus clone that shows high expression level further increases by being transfected into the Sf9 cell.At ExpresSF
It is high-caliber almost without the protein of degrading that expression among the cells (Protein Sciences Corp., Meriden, Connecticut, USA) provides.Cell lysate is loaded to fills single nickel salt and uses 50mM HEPES pH 7.5, the pillar HiTrap of 0.5M sodium-chlor and 10mM imidazoles balance
TMChelating Sepharose HP (Amersham Biosciences).The constantly HEPES damping fluid of increase imidazoles amount/sodium-chlor wash-out of the protein of catching, and pass through in 50mMHEPES pH 7.5,10% glycerine and 1mM DTT, to dialyse to be further purified.
4.FAK phosphorylation level
By the quantitative FAK of sandwich ELISA at Tyr397 place phosphorylation level.Mouse breast cancer 4T1 cell (1x10
5) add in the hole of 96-well culture plate and with the formula I compound that has or do not exist different concns and in the eagle substratum of Dulbecco ' the s improvement that contains 10%FBS, hatched 1 hour.Remove substratum and cell is being contained 1%NP-40,0.25% Sodium desoxycholate, 150mM NaCl, 1mM EDTA, 1mM PMSF, 1mM Na
3VO
4, 1mM NaF, 1 μ g/mL AKOLINE, 1 μ g/mL leupeptin and 1 μ g/mL pepstatin 200 μ L 50mMTris-HCl, cracking among the pH 7.4.After centrifugal, supernatant liquor comes quantitative phosphorylation FAK and total FAK with sandwich ELISA.Cell pyrolysis liquid places 4 ℃ of the flat elisa plates in 96-hole lower 18 hours, this plate resists-FAK antibody (clone 77 with the 4 μ g/mL mouse monoclonals in 100 μ L/ holes in advance, BectonDickinson Transduction Laboratories) 50mM Tris-HCl, pH 9.5, the solution of 150mM sodium-chlor is coated, and seals 2 hours under 300 μ L BlockAce (DainipponPharmaceuticals Co.) room temperatures of water dilution in 1: 4.With TBSN (20mM Tris-HCl, pH8.3, contain 300mM NaCl, 0.1%SDS and 0.05%NP-40) washing after, with resisting-FAK polyclonal antibody (#65-6140 of 100 μ L, 1 μ g/ml, Upstate Biology Inc.) detect total FAK, and phosphorylation FAK with 100 μ L, 0.25 μ g/ μ L anti--the BlockAce solution (water dilution in 1: 10) of phosphorylation FAK (Y397) antibody (Affinity BioReagents, #OPA1-03071) detects.Hatched under the room temperature 1 hour, dull and stereotyped with after the TBSN washing, add 100 μ L and resist-rabbit igg (#65-6140, Zymed LaboratoliesInc.) with the biotinylation that following BlockAce dilutes at 1: 2000, incubated at room 1 hour, the dilution in 1: 10 of wherein said BlockAce water.After the TBSN washing, with ABTS solution substrate reagent box (#00-2011, Zymed Lobolatories Inc.) colour developing.Hatch the optical density of measuring the 405nm place after 20 minutes under the room temperature.Mensuration causes FAK phosphorylation level decline 50% (IC
50) compound concentration.In this assay method, formula I compound reduces the IC of phosphorylation
50＜1 μ M.Embodiment 190,198 and 210 shows IC
50Value is respectively 0.44 μ M, 0.043 μ M and 0.01 μ M.
5. non-anchorage dependence growth of tumour cell assay method
With mouse breast cancer 4T1 cell (5x10
3) place 100 μ L in the 96-hole Ultra low Attachment plate (#3474, Corning Inc.) to contain the eagle substratum of the Dulbecco improvement of 10%FBS.Cell cultures 2 hours, adding DMSO final concentration are 0.1% different concns inhibition.After 48 hours, Growth of Cells is measured with cell counting test kit-8 (Wako Pure Chemical), and this test kit uses water-soluble tetrazolium salts WST8.Every hole adds 20 μ L reagent and continued culturing cell 2 hours.Measure optical density(OD) at 450nm.Cause that 50% growth inhibiting compound concentration can measure thus.Embodiment 204,213 and 206 shows IC
50Value is respectively 0.4 μ M, 0.016 μ M and 0.09 μ M.
Therefore compound of the present invention can be used for preventing or treating disorder or the disease of having an effect by ZAP-70 inhibition and/or Syk inhibition, T lymphocyte for example, bone-marrow-derived lymphocyte, disease or the disorder of mastocyte and/or eosinophilic granulocyte mediation, the for example allotransplantation of acute or chronic organ or tissue or xenograft rejection, atherosclerosis, because blood vessel injury such as revascularization, vascular restenosis, hypertension, in heart failure, chronic pulmonary is blocked the angiemphraxis that disease causes, CNS disease such as alzheimer's disease or amyotrophic lateral sclerosis, cancer, infectious diseases such as AIDS, septic shock or adult's Respiratory distress syndrome, local asphyxia/reperfusion injury is myocardial infarction for example, apoplexy, the intestines local asphyxia, renal failure or hemorrhagic shock, or traumatic shock.Reagent of the present invention also can be used for treating and/or preventing acute or chronic inflammatory diseases or disorder or autoimmune disease rheumatoid arthritis for example, osteoarthritis, systemic lupus erythematous, struma lymphomatosa (Hashimoto ' s thyroidis), multiple sclerosis, myasthenia gravis, diabetes (I type and II type) and associated disorder, respiratory disease is asthma or inflammatory hepatic injury for example, the inflammatory glomerular injury, the skin table disease of immune-mediated disorder or disease, inflammatory and hyperplasia dermatoses are (such as psoriasis, atopic dermatitis, supersensitivity contact dermatitis, pungency contact dermatitis and eczema, seborrheic dermatitis), inflammatory eye disease such as xerodermosteosis, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn disease or ulcerative colitis.
The disease that the signal cascade dysfunction that compound of the present invention also can be used for preventing or treatment is relevant with FAK causes, tumour for example, for example brain and other central nerve neuroma (such as meninx, brain, notochord, cranium nervus lateralis tumour and other parts central nervous system cancer for example glioblastoma or marrow blastoma); Head and/or neck cancer; Breast tumor; Recycle system tumour (for example vascular tissue of organ, vascular tumor and Tumor-assaciated in heart, vertical diaphragm and pleura and other thorax); Excretory system tumour (such as kidney, renal plevis, ureter, bladder etc. and non-specific urinary organ); Gastroenteric tumor (for example esophagus, stomach, small intestine, colon, colorectum, second shape rectum connection section, rectum, anus and anus road), involve liver and stones in intrahepatic bile duct, gall-bladder, etc. and non-specific biliary tract part, pancreas etc. reach Alimentary tumour); Head and neck; Oral cavity (other position of lip, tongue, gums, mouthful end, palate and mouthful other parts, the parotid gland and sialisterium other parts, tonsilla, oropharynx, nasopharynx, piriform sinus, laryngopharynx and lip, oral cavity and pharynx); Genital system tumor (for example tumour of vulva, vagina, uterine cervix, body of uterus, uterus, ovary and other female reproductive organ's region of interest, placenta, penis, prostate gland, testis and other male reproductive organ region of interest); Respiratory tract neoplasms (for example nasal cavity and middle ear, attached hole, larynx, tracheae, segmental bronchus and lung, for example small cell lung cancer or non--small cell lung cancer); Skeletal system tumour (for example bone and four limbs official's rank cartilage, bone articular cartilage and other position); Dermatoma (for example malignant melanoma of skin, skin non-black element knurl, rodent ulcer, cutaneous squamous cell carcinoma, mesothelioma, kaposi's sarcoma); And comprise other tissue tumor, comprise peripheral nerve and autonomic nervous system, reticular tissue and soft tissue, retroperitoneum and peritonaeum, eye and appendicle, Tiroidina, suprarenal gland, with other incretory gland and dependency structure, secondary and non-specific malignant lymph node anything superfluous or useless, breathe and the secondary malignant growth of Digestive tract and the pernicious anything superfluous or useless of secondary at other position, blood and lymphsystem tumor are (for example: Hodgkin, non Hodgkin lymphoma, Burkitt ' s lymphoma, the AIDS-associated lymphoma, pernicious immunoproliferative disease, multiple myeloma and malignant plasma cell anything superfluous or useless, Lymphocytic leukemia, the acute and chronic myeloid leukemia, the acute and chronic Lymphocytic leukemia, monocytic leukemia, other non-specific cellular type leukemia, non-specific type chronic myeloid leukemia, other and non-specific malignant lymph node, hematopoiesis and related tissue's anything superfluous or useless are for example filled the air large celllymphoma, t cell lymphoma or epidermis t cell lymphoma) effect arranged.Bone marrow cancer comprises acute and chronic myelomatosis.
Above and hereinafter, when mentioning tumour, tumor disease, cancer or cancer, alternatively or in addition also refer to the metastasis of cancer in primitive organ or tissue and/or any other position, no matter what the position of tumour and/or metastasis of cancer is.
Can use the present composition with any conventional route, particularly stomach other places the form of Injectable solution or suspension (for example with), ground (for example orally in the intestines, for example with tablet or capsule form), topical application, for example with the form of washing lotion, gelifying agent, ointment or frost, or with the form of nasal drop or suppository.The pharmaceutical composition that comprises reagent of the present invention and at least a pharmaceutically acceptable carrier or thinner can be used ordinary method, by producing with pharmaceutically acceptable carrier or mixing diluents.Orally administered unit dosage for example comprises from about 0.1mg to about 500mg active substance.Topical application refers to for example application to skin.The another kind of form of topical application is for eye.
Formula I compound can with free form or the form of pharmacologically acceptable salt, for example be used as mentioned above.
This class salt can and demonstrate and the activity of free cpds with magnitude with the ordinary method preparation.
Consistent with the front, the present invention also provides:
(1) formula I compound or pharmaceutically acceptable salt thereof is as medicine;
(2) formula I compound or pharmaceutically acceptable salt thereof as ZAP-70, FAK and/or Syk tyrosine kinase inhibitor, for example is used for previously described arbitrary specific adaptations disease;
(3) comprise formula I compound or pharmaceutically acceptable salt thereof, and comprise the pharmaceutical composition of one or more pharmaceutically acceptable diluents or carrier, for example be used for previously described arbitrary indication;
(4) method of any as previously mentioned specific adaptations disease for the treatment of in its experimenter of needs comprises the formula I compound or pharmaceutically acceptable salt thereof of using significant quantity;
(5) purposes of formula I compound or pharmaceutically acceptable salt thereof is for the preparation for the treatment of or prevention ZAP-70, FAK and/or Syk tyrosine-kinase enzyme activation works therein or the medicine of relevant disease; For example as discussed above.
Compound of the present invention can be used as independent activeconstituents or together uses or use in the immunomodulatory therapy with other medicine to anti-tumor disease, inflammatory disorder.For example, compound of the present invention can with the effective promoting agent of above-mentioned various diseases is united use, described promoting agent is S-Neoral, rapamycin or ascosin for example, or their immunosuppression analogue or derivative such as cyclosporin A, CYCLOSPORIN G, Isa tx247, FK-506, sirolimus or everolimus; CCI-779, ABT578, AP23573, corticoid, prednisone for example, endoxan, azathioprine, methotrexate, the gold preparation, sulfasalazine, antimalarial drug, Leflunomide, mizoribine, mycophenolic acid, mycophenlate mofetil, 15-deoxidation Antibiotic BMG-162aF2, has the EDG receptor stimulant (for example FTY720 or its analogue) that promotes the lymphocyte homing activity, inhibitive ability of immunity monoclonal antibody, for example leukocyte receptors MHC for example, CD2, CD3, CD4, CD7, CD25, CD28, CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-1, the monoclonal antibody of VLA-4 or their parts; Or other immune regulative compound, for example CTLA4Ig.
Formula I compound also can advantageously be united use with other anti-proliferative agent.This class anti-proliferative agent includes but not limited to aromatase inhibitor; antiestrogen; the topoisomerase I inhibitor; Topoisomerase II inhibitors; microtubule active agent; alkylating reagent; histone deacetylase inhibitors; farnesyl tranfering enzyme inhibitor; cox 2 inhibitor; the MMP inhibitor; mTOR inhibitors; antineoplastic antimetabolite; platinic compound; reduce the compound of protein kinase activity and the compound of angiogenesis inhibitor; short sexual gland releasing hormone agonist; antiandrogen; bengamides; bis phosphoric acid salt (bisphosphonates); anti-hyperplasia antibody and Temozoromide
Term used herein " aromatase inhibitor " relates to and suppresses estrogen production and be about to the compound that substrate Androstenedione and testosterone are separately converted to oestrone and estradiol.This term includes but not limited to steroid, especially Exemestane and Formestane, in particular on-steroidal, especially ammonia Shandong Ban Te, R 83842, Arensm, Anastrozole and very in particular letrozole (letrozole).The present composition that comprises antineoplastic agent (it is aromatase inhibitor) can be used in particular for treating the mammary tumor of hormone receptor positive.
Term used herein " antiestrogen " relates at the compound of Estrogen Receptor to estrogenic antagonist.This term includes but not limited to tamoxifen, fulvestrant, raloxifene and RALOXIFENE HCL.
Term used herein " topoisomerase I inhibitor " includes but not limited to topotecan, irinotecan, 9-nitrocamptothecin and macromolecular camptothecine conjugate PNU-166148 (compd A 1 in WO99/17804).
Term used herein " topoisomerase II preparation " includes but not limited to that antracyclines, Zorubicin (comprise Liposomal formulation, for example AELYX
TM), day care anthraquinone and losoxantrone and etoposide and the teniposide (teniposide) of pidorubicin, O-Demethyldaunomycin and nemorubicin, Anthraquinones.
Term used herein " microtubule active agent " relates to microtubule and stablizes and microtubule destabilizer, include, but are not limited to taxol and the Taxotere of taxanes, catharanthus alkaloid, vincaleucoblastine for example, vincaleucoblastine vitriol particularly, vincristine(VCR), particularly leucocristine sulfate, and vinorelbine, discodermolide and esperamicin such as epothilone B and D.
Term used herein " alkylating reagent " includes but not limited to endoxan, ifosfamide and melphalan.
Term used herein " histone deacetylase inhibitors " relates to the inhibition of histone deacetylase and has the compound of anti-proliferative activity.
Term used herein " farnesyl moves enzyme inhibitors " relates to the compound that suppresses farnesyl transferase and have anti-proliferative activity.
Term used herein " cox 2 inhibitor " relates to for example celecoxib of the compound that suppresses 2 type epoxidase (COX-2) and have anti-proliferative activity
VIOXX
And lumiracoxib (COX189).
Term used herein " MMP inhibitor " relates to the compound that suppresses matrix metalloproteinase (MMP) and have anti-proliferative activity.
Term used herein " antineoplastic antimetabolite " includes but not limited to the salt of 5 FU 5 fluorouracil, Ftorafur, capecitabine, carat sharp flat, cytosine arabinoside, fludarabine phosphoric acid salt, Fluracil, gemcitabine, Ismipur, hydroxyurea, methotrexate, edatrexate and this compounds, and ZD 1694 (RALTITREXED
TM), LY231514 (ALIMTA
TM), LY264618 (LOMOTREXOL
TM) and OGT719.
Term used herein " platinic compound " includes but not limited to Carboplatin, cis-platinum and RP-54780.
Term used herein " reduces compound and other angiogenesis inhibitor compound of protein kinase activity " and includes but not limited to reduce for example vascular endothelial growth factor (VEGF), Urogastron (EGF), c-Src, protein kinase C, platelet-derived growth factor (PDGF), the Bcr-Abl Tyrosylprotein kinase, c-kit, compound and the angiogenesis inhibitor compound with reduction protein kinase activity other mechanism of action in addition that Flt-3 and insulin-like growth factor I receptor (IGF-IR) and cell cycle protein dependent kinase (CDKs) are active.
The compound that reduces the VEGF activity particularly suppresses vegf receptor, especially the compound of the tyrosine kinase activity of vegf receptor, and in conjunction with the compound of VEGF, particularly those classification and be disclosed in particularly compound, protein and monoclonal antibody among WO 98/35958 (describing formula I compound), WO 00/09495, WO00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 01/55114, WO 01/58899 and the EP 0 769 947; Those by people such as M.Prewett at Cancer Research
59(1999) 5209-5218, by people such as F.Yuan at Proc.Natl.Acad.Sci.USA, vol.93, pp.14765-14770, December 1996, by people such as Z.Zhu at Cancer Res.58,1998,3209-3214, with by people such as J.Mordenti at Toxicologic Pathology, vol.27, no.1, pp 14-21 is described in 1999; At WO 00/37502 and WO 94/10202; Angiostatin
TM, by people such as M.S.O ' Reilly, Cell 79,1994, and 315-328 describes; And Endostatin
TM, by people such as M.S.O ' Reilly, Cell 88,1997, the described compound of 277-285;
The compound that reduces the EGF activity especially suppresses the EGF acceptor, especially the compound of EGF receptor tyrosine kinase activity, and in conjunction with the compound of EGF, and particularly those classification and be disclosed in particularly WO 97/02266 (describing formula IV compound), EP 0 564 409, WO99/03854, EP 0520722, EP 0,566 226, EP 0,787 722, EP 0,837 063, WO98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and especially at the compound of WO 96/33980;
The compound of reduction c-Src activity includes but not limited to compound and the SH2 interaction inhibitor such as undefined inhibition c-Src protein tyrosine kinase activity, and is disclosed in WO97/07131and WO97/08193 such as those;
The compound that suppresses the c-Src protein tyrosine kinase activity includes but not limited to belong to pyrrolopyrimidine, especially pyrrolo-[2,3-d] pyrimidine, purine, pyrazolopyrimidine, especially pyrazolo [3,4-d] pyrimidine, pyrazolopyrimidine, especially pyrazolo [3,4-d] compound of pyrimidine and Pyridopyrimidine, especially pyrido [2,3-d] pyrimidine structure class.Preferably, this term relates to those disclosed compounds in WO 96/10028, WO 97/28161, WO97/32879 and WO97/49706;
Especially those are disclosed in and are the staurosporine derivatives of inhibitors of protein kinase C among the EP 0 296 110 (describing the medicine preparation at WO 00/48571) compound that reduces protein kinase C activity;
Other specific compound that reduces protein kinase activity and may be used in combination with the present invention is Imatinib
PKC412, Iressa
TM(ZD1839), PKI166, PTK787, ZD6474, GW2016, CHIR-200131, CEP-7055/CEP-5214, CP-547632 and KRN-633;
Have the angiogenesis inhibitor compound that reduces protein kinase activity other mechanism of action in addition and include but not limited to, for example thalidomide (THALOMID), celecoxib (Celebrex), SU5416 and ZD6126.
Term used herein " GnRF agonist " includes but not limited to abarelix, Coserelin and goserelin acetate.Coserelin is disclosed in US 4,100, in 274.
Term used herein " antiandrogen " includes but not limited to can be such as US 4,636, the bicalutamide (CASODEX of disclosed such preparation in 505
TM).
The derivative that term " bengamides " relates to bengamides and has anti-hyperplasia character.
Term used herein " bis phosphoric acid salt " includes but not limited to etridonic acid, chlorine phosphoric acid (clodronic acid) in the wrong, fills in phosphoric acid (risedronic acid) and Zoledronate (zoledronic acid) for Shandong phosphoric acid (tiludronic acid), Pamidronic Acid (pamidronicacid), Alendronic Acid (alendronic acid), Eibar phosphoric acid (ibandronic acid), profit.
Term used herein " anti-hyperplasia antibody " includes but not limited to Herceptin (Herceptin
TM), Si Tumanbu-DM1, erlotinib (Tarceva
TM), bevacizu mab (Avastin
TM), sharp appropriate uncommon agate
PRO64553 (anti-CD 40) and 2C4 antibody.
Structure by the definite promoting agent of code name, generic name or trade(brand)name can obtain from the current edition of standard outline " TheMerck Index " or from for example Patents International database (such as IMSWorld Publications).
With aforementioned consistent, the present invention also further provides following aspect:
(6) method as defined above for example comprises simultaneously or successively a) formula I compound or pharmaceutically acceptable salt thereof and the b of co-administered treatment significant quantity) the second medicine, described the second medicine for example is used for previously described arbitrary specific adaptations disease.
(7) comprise for example composition of the treatment significant quantity of formula I compound or pharmaceutically acceptable salt thereof and the second medicine of ZAP-70, FAK and/or Syk tyrosine kinase inhibitor, wherein said the second medicine is for example as above disclosed.
If ZAP-70, FAK and/or Syk tyrosine kinase inhibitor, for example formula I compound and other are when for example inhibitive ability of immunity/immunomodulatory as disclosed above, anti-inflammatory or antineoplastic agent are co-administered, the medicine of being used altogether or the dosage of reagent certainly will be according to the types of institute's concomitant medication or reagent, or used specific medication or reagent, or the change such as subject disease.
Representational FAK inhibitor is the compound of embodiment 187-203 and 209-212.
Sequence table
＜110〉Novannis company
＜120〉pyrimidine derivatives
<130>4-32366A
<150>GB 0206215.6
<151>2002-03-15
<160>4
＜170〉PatentIn version 3 .1
<210>1
<211>15
<212>PRT
＜213〉artificial sequence
<220>
＜223〉LAT-11 is for being used for the artificial sequence of ZAP-70 kinase assay
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉X=L (+)-biotinylated amino caproyl
<400>1
Xaa Glu Glu Gly Ala Pro Asp Tyr Glu Asn Leu Gln Gln Leu Asn
1 5 10 15
<210>2
<211>12
<212>PRT
＜213〉artificial sequence
<220>
＜223〉Biot-Y397 is for being used for the sequence of FAK assay method
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉vitamin H
<400>2
Xaa Ser Glu Thr Asp Asp Tyr Ala Glu Ile Ile Asp
1 5 10
<210>3
<211>21
<212>DNA
＜213〉artificial sequence
<220>
＜223〉for the preparation of the PCR primer of human FAK cDNA
<400>3
atggcagctg cttaccttga c 21
<210>4
<211>21
<212>DNA
＜213〉artificial sequence
<220>
＜223〉for the preparation of the PCR primer of human FAK cDNA
<400>4
tcagtgtggt ctcgtctgcc c 21
Claims (6)
1. the formula I compound of free form or salt form,
Wherein
X is=CR
0-;
R
0Hydrogen;
R
2Be-SO
2N (R
10) R
11
R
1And R
3In each be hydrogen independently; Hydroxyl; C
1-C
8Alkyl; C
2-C
8Alkenyl; C
3-C
8Cycloalkyl; C
3-C
8Cycloalkyl-C
1-C
8Alkyl; Hydroxyl C
1-C
8Alkyl; C
1-C
8Alkoxy C
1-C
8Alkyl; Hydroxyl C
1-C
8Alkoxy C
1-C
8Alkyl; Randomly can be by hydroxyl, C on ring
1-C
8Alkoxyl group, carboxyl or C
1-C
8The aryl C that alkoxy carbonyl replaces
1-C
8Alkyl;
Perhaps R
1And R
3In each be halogen, halo-C independently
1-C
8Alkyl; C
1-C
8Alkoxyl group, halo-C
1-C
8Alkoxyl group, hydroxyl C
1-C
8Alkoxyl group; C
1-C
8Alkoxy C
1-C
8Alkoxyl group; Aryl; Aryl C
1-C
8Alkoxyl group; Heteroaryl; Heteroaryl-C
1-C
4Alkyl; 5 to 10 yuan of heterocycles; Nitro; Carboxyl; C
2-C
8Alkoxy carbonyl; C
2-C
8Alkyl-carbonyl;-N (C
1-C
8Alkyl) C (O) C
1-C
8Alkyl;-N (R
10) R
11-CON (R
10) R
11Or-C
1-C
4-alkylidene group-SO
2N (R
10) R
11R wherein
10And R
11In each be hydrogen independently; Hydroxyl; C
1-C
8Alkyl; C
2-C
8Alkenyl; C
3-C
8Cycloalkyl; C
3-C
8Cycloalkyl-C
1-C
8Alkyl; C
1-C
8Alkoxy C
1-C
8Alkyl; Hydroxyl C
1-C
8Alkoxy C
1-C
8Alkyl; Hydroxyl C
1-C
8Alkyl; (C
1-C
8Alkyl)-carbonyl; Randomly can be by hydroxyl, C on ring
1-C
8Alkoxyl group, carboxyl or C
2-C
8The aryl C that alkoxy carbonyl replaces
1-C
8Alkyl; Or 5 to 10 yuan of heterocycles;
R
4Hydrogen;
R
5Hydrogen; Halogen; C
1-4Alkyl; Or CF3;
R
6Hydrogen;
R
7, R
8And R
9In each be hydrogen independently; Hydroxyl; C
1-C
8Alkyl; C
2-C
8Alkenyl; Halo-C
1-C
8Alkyl; C
1-C
8Alkoxyl group; C
3-C
8Cycloalkyl; C
3-C
8Cycloalkyl C
1-C
8Alkyl; Aryl C
1-C
8Alkyl;-Y-R
12, wherein Y is direct key or an O, and R
12Be a replacement or unsubstitutedly comprise 1,2 or 3 heteroatomic 5,6 or 7 yuan of heterocycle that are selected from N, O and S; Carboxyl, (C
1-C
8Alkoxyl group)-carbonyl;-N (C
1-8Alkyl)-CO-NR
10R
11-CONR
10R
11-N (R
10) (R
11);-SO
2N (R
10) R
11R
7And R
8Or R
8And R
9, form with the carbon atom that connects with their respectively and comprise 1,2 or 3 the heteroatomic 5 or 6 yuan of heteroaryl that is selected from N, O and S; Or 5 or 6 yuan of carbocyclic rings;
Wherein any alkyl, alkoxyl group, alkenyl, cycloalkyl, heterocycle, aryl or heteroaryl can not be substituted or by one or more halogens that are selected from; OH; C
1-C
8Alkyl; C
1-C
8Alkoxyl group; Nitro; Cyano group; COOH; Formamyl; C (NH
2)=NOH;-N (R
10) R
11C
3-C
6Cycloalkyl; 3 to 7 yuan of heterocycles; Phenyl; Phenyl-C
1-4Alkyl; The substituting group of 5 or 6 yuan of heteroaryls replaces.
2. compound according to claim 1, wherein R at the most
1Or R
3One of be-CON (R
10) R
11
3. compound according to claim 1, it is formula X
4Compound,
R wherein
2, R
5, R
7, R
8And R
9Be as claimed in claim 1 definition.
For generation of according to claim 1 to 3 each the methods of formula I compound, it comprises the compound with Formula Il:
R wherein
1, R
2, R
3, R
4, R
5, R
6Be as claimed in claim 1 definition with X, Y is leavings group; Step with the reaction of the compound of Formula Il I:
R wherein
7, R
8And R
9Be as claimed in claim 1 definition;
And reclaim the free form obtain or the formula I compound of salt form, and as required, will change into the target salt form with the formula I compound that free form obtains, or vice versa.
5. pharmaceutical composition, it comprises according to claim 1 to 3 each formula I compound or pharmaceutically acceptable salt thereofs, and also comprises one or more pharmaceutically acceptable carrier or thinner.
6. free form or pharmaceutical acceptable salt according to claim 1 to 3 each the purposes of formula I compound, for the preparation for the treatment of or prevent wherein ZAP-70, FAK and/or Syk tyrosine kinase activity disease that play a role or relevant or the medicine of illness.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0206215.6A GB0206215D0 (en) | 2002-03-15 | 2002-03-15 | Organic compounds |
| GB0206215.6 | 2002-03-15 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA038061015A Division CN1697830A (en) | 2002-03-15 | 2003-03-14 | Pyrimidine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101830889A CN101830889A (en) | 2010-09-15 |
| CN101830889B true CN101830889B (en) | 2013-01-02 |
Family
ID=9933092
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA038061015A Pending CN1697830A (en) | 2002-03-15 | 2003-03-14 | Pyrimidine derivatives |
| CN2011102019723A Pending CN102336716A (en) | 2002-03-15 | 2003-03-14 | Pyrimidine derivatives |
| CN2010101974578A Expired - Lifetime CN101830889B (en) | 2002-03-15 | 2003-03-14 | Pyrimidine derivatives |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA038061015A Pending CN1697830A (en) | 2002-03-15 | 2003-03-14 | Pyrimidine derivatives |
| CN2011102019723A Pending CN102336716A (en) | 2002-03-15 | 2003-03-14 | Pyrimidine derivatives |
Country Status (25)
| Country | Link |
|---|---|
| US (3) | US7943627B2 (en) |
| EP (2) | EP1487805B1 (en) |
| JP (1) | JP4362377B2 (en) |
| KR (1) | KR100618037B1 (en) |
| CN (3) | CN1697830A (en) |
| AU (1) | AU2003227070B2 (en) |
| BR (1) | BR0308461A (en) |
| CA (1) | CA2479133C (en) |
| CO (1) | CO5640117A2 (en) |
| CY (2) | CY1113118T1 (en) |
| DK (2) | DK1487805T3 (en) |
| EC (1) | ECSP045294A (en) |
| ES (2) | ES2387270T3 (en) |
| GB (1) | GB0206215D0 (en) |
| HK (1) | HK1151292A1 (en) |
| IL (2) | IL163817A0 (en) |
| MX (1) | MXPA04009058A (en) |
| NO (1) | NO20044374L (en) |
| NZ (1) | NZ535109A (en) |
| PL (2) | PL370834A1 (en) |
| PT (2) | PT1487805E (en) |
| RU (1) | RU2324684C2 (en) |
| SI (2) | SI2308855T1 (en) |
| WO (1) | WO2003078404A1 (en) |
| ZA (1) | ZA200406709B (en) |
Families Citing this family (184)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2463989C (en) * | 2001-10-17 | 2012-01-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pyrimidine derivatives, pharmaceutical compositions containing these compounds, the use thereof and process for the preparation thereof |
| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| GB0206215D0 (en) * | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
| CA2489648A1 (en) * | 2002-06-17 | 2003-12-24 | Smithkline Beecham Corporation | Chemical process |
| DK1534286T3 (en) | 2002-07-29 | 2010-04-26 | Rigel Pharmaceuticals Inc | Methods for treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds |
| US7109337B2 (en) | 2002-12-20 | 2006-09-19 | Pfizer Inc | Pyrimidine derivatives for the treatment of abnormal cell growth |
| PL379330A1 (en) | 2002-12-20 | 2006-08-21 | Pfizer Products Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
| US7514446B2 (en) | 2003-02-20 | 2009-04-07 | Smithkline Beecham Corporation | Pyrimidine compounds |
| JP2006519846A (en) * | 2003-03-10 | 2006-08-31 | シェーリング コーポレイション | Heterocyclic kinase inhibitors: methods of use and synthesis |
| GB0305929D0 (en) * | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
| GB0319227D0 (en) * | 2003-08-15 | 2003-09-17 | Novartis Ag | Organic compounds |
| PT1656372E (en) | 2003-07-30 | 2013-06-27 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds for use in the treatment or prevention of autoimmune diseases |
| NZ585188A (en) * | 2003-08-15 | 2011-09-30 | Novartis Ag | 2,4-Pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
| AU2004268614C1 (en) | 2003-08-27 | 2010-10-28 | Ophthotech Corporation | Combination therapy for the treatment of ocular neovascular disorders |
| GB0321710D0 (en) * | 2003-09-16 | 2003-10-15 | Novartis Ag | Organic compounds |
| WO2005026130A1 (en) * | 2003-09-18 | 2005-03-24 | Novartis Ag | 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders |
| AU2005205167A1 (en) * | 2004-01-16 | 2005-07-28 | Novartis Ag | 2, 4 - diaminopyrimidines and their use for inducing cardiomyogenesis |
| US8057815B2 (en) * | 2004-04-19 | 2011-11-15 | Portola Pharmaceuticals, Inc. | Methods of treatment with Syk inhibitors |
| EP1758887A1 (en) | 2004-05-14 | 2007-03-07 | Pfizer Products Incorporated | Pyrimidine derivatives for the treatment of abnormal cell growth |
| CA2566332A1 (en) | 2004-05-14 | 2005-11-24 | Pfizer Products Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
| JP2007537235A (en) | 2004-05-14 | 2007-12-20 | ファイザー・プロダクツ・インク | Pyrimidine derivatives for the treatment of abnormal cell proliferation |
| NZ588896A (en) * | 2004-08-25 | 2012-05-25 | Targegen Inc | Heterocyclic compounds and methods of use |
| GB0419161D0 (en) * | 2004-08-27 | 2004-09-29 | Novartis Ag | Organic compounds |
| GB0419160D0 (en) * | 2004-08-27 | 2004-09-29 | Novartis Ag | Organic compounds |
| CA2580838A1 (en) * | 2004-09-27 | 2006-04-06 | Amgen Inc. | Substituted heterocyclic compounds and methods of use |
| US7557207B2 (en) | 2004-11-24 | 2009-07-07 | Rigel Pharmaceuticals, Inc. | Spiro 2,4-pyrimidinediamine compounds and their uses |
| MY169441A (en) * | 2004-12-08 | 2019-04-11 | Janssen Pharmaceutica Nv | 2,4, (4,6) pyrimidine derivatives |
| US7968574B2 (en) | 2004-12-28 | 2011-06-28 | Kinex Pharmaceuticals, Llc | Biaryl compositions and methods for modulating a kinase cascade |
| PL1836169T3 (en) | 2004-12-28 | 2012-07-31 | Kinex Pharmaceuticals Llc | Compositions and methods of treating cell proliferation disorders |
| AU2006206458B2 (en) | 2005-01-19 | 2012-10-25 | Rigel Pharmaceuticals, Inc. | Prodrugs of 2,4-pyrimidinediamine compounds and their uses |
| US7772191B2 (en) | 2005-05-10 | 2010-08-10 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
| US20070203161A1 (en) | 2006-02-24 | 2007-08-30 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| NZ563454A (en) | 2005-06-08 | 2011-03-31 | Rigel Pharmaceuticals Inc | 2,4-diaminopyrimidine derivatives for inhibition of the JAK pathway |
| WO2007006926A2 (en) * | 2005-07-11 | 2007-01-18 | Sanofi-Aventis | Novel 2,4-dianilinopyrimidine derivatives, the preparation thereof, their use as medicaments, pharmaceutical compositions and, in particular, as ikk inhibitors |
| FR2888239B1 (en) * | 2005-07-11 | 2008-05-09 | Sanofi Aventis Sa | NOVEL 2,4-DIANILINOPYRIMIDINE DERIVATIVES, THEIR PREPARATION AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND IN PARTICULAR AS INHIBITORS OF IKK |
| US8133900B2 (en) * | 2005-11-01 | 2012-03-13 | Targegen, Inc. | Use of bi-aryl meta-pyrimidine inhibitors of kinases |
| US8604042B2 (en) | 2005-11-01 | 2013-12-10 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
| MY167260A (en) * | 2005-11-01 | 2018-08-14 | Targegen Inc | Bi-aryl meta-pyrimidine inhibitors of kinases |
| EP1966207A2 (en) | 2005-12-21 | 2008-09-10 | Pfizer Products Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
| WO2007085540A1 (en) * | 2006-01-27 | 2007-08-02 | Glaxo Group Limited | 1h-indaz0l-4-yl-2 , 4-pyrimidinediamine derivatives |
| ES2622493T3 (en) | 2006-02-24 | 2017-07-06 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibiting the JAK route |
| PE20080697A1 (en) | 2006-05-03 | 2008-08-05 | Boehringer Ingelheim Int | BENZONITRILE DERIVATIVES SUBSTITUTED WITH GLUCOPYRANOSIL, PHARMACEUTICAL COMPOSITIONS CONTAINING COMPOUNDS OF THIS TYPE, THEIR USE AND PROCEDURE FOR THEIR MANUFACTURE |
| CN101506175A (en) * | 2006-06-15 | 2009-08-12 | 贝林格尔·英格海姆国际有限公司 | 2-anilino-4-(heterocyclic)amino-pyrimidines as inhibitors of protein kinase C-alpha |
| DK2041071T3 (en) * | 2006-06-29 | 2014-09-01 | Kinex Pharmaceuticals Llc | BIARLYL COMPOSITIONS AND PROCEDURES FOR MODULATING A CHINA CASE |
| AU2007265373B2 (en) | 2006-06-29 | 2013-02-21 | Atnx Spv, Llc | Biaryl compositions and methods for modulating a kinase cascade |
| JP5161233B2 (en) * | 2006-10-19 | 2013-03-13 | ライジェル ファーマシューティカルズ， インコーポレイテッド | 2,4-pyrimidinamine derivatives as inhibitors of JAK kinase for the treatment of autoimmune diseases |
| WO2008051547A1 (en) | 2006-10-23 | 2008-05-02 | Cephalon, Inc. | Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and c-met inhibitors |
| CN101616895A (en) | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
| KR101149295B1 (en) * | 2006-12-08 | 2012-07-05 | 아이알엠 엘엘씨 | Compounds as protein kinase inhibitors |
| TWI457336B (en) | 2006-12-28 | 2014-10-21 | Kinex Pharmaceuticals Llc | Composition and methods for modulating a kinase cascade |
| US7939529B2 (en) | 2007-05-17 | 2011-05-10 | Kinex Pharmaceuticals, Llc | Process for the preparation of compositions for modulating a kinase cascade and methods of use thereof |
| US7935697B2 (en) | 2006-12-28 | 2011-05-03 | Kinex Pharmaceuticals, Llc | Compositions for modulating a kinase cascade and methods of use thereof |
| TW200902010A (en) * | 2007-01-26 | 2009-01-16 | Smithkline Beecham Corp | Anthranilamide inhibitors of aurora kinase |
| TW200840581A (en) * | 2007-02-28 | 2008-10-16 | Astrazeneca Ab | Novel pyrimidine derivatives |
| DK2134689T3 (en) | 2007-03-16 | 2014-06-30 | Scripps Research Inst | Focal adhesion kinase inhibitors |
| US8642067B2 (en) | 2007-04-02 | 2014-02-04 | Allergen, Inc. | Methods and compositions for intraocular administration to treat ocular conditions |
| CA2684470C (en) | 2007-04-16 | 2016-02-09 | Hutchison Medipharma Enterprises Limited | Pyrimidine derivatives |
| EP2146779B1 (en) | 2007-04-18 | 2016-08-10 | Pfizer Products Inc. | Sulfonyl amide derivatives for the treatment of abnormal cell growth |
| TWI389893B (en) * | 2007-07-06 | 2013-03-21 | Astellas Pharma Inc | Di (arylamino) ary1 compound |
| US8124605B2 (en) | 2007-07-06 | 2012-02-28 | Kinex Pharmaceuticals, Llc | Compositions and methods for modulating a kinase cascade |
| CL2008002427A1 (en) | 2007-08-16 | 2009-09-11 | Boehringer Ingelheim Int | Pharmaceutical composition comprising 1-chloro-4- (bd-glucopyranos-1-yl) -2- [4 - ((s) -tetrahydrofuran-3-yloxy) benzyl] -benzene combined with 1 - [(4-methylquinazolin- 2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (r) -aminopiperidin-1-yl) xanthine; and its use to treat type 2 diabetes mellitus. |
| US8440681B2 (en) | 2007-08-28 | 2013-05-14 | Irm Llc | 2-biphenylamino-4-aminopyrimidine derivatives as kinase inhibitors |
| CA2710118A1 (en) | 2007-12-20 | 2009-07-02 | Cellzome Limited | Sulfamides as zap-70 inhibitors |
| US20100317663A1 (en) * | 2008-02-19 | 2010-12-16 | Jerry Leroy Adams | Anilinopyridines as inhibitors of fak |
| US8138339B2 (en) | 2008-04-16 | 2012-03-20 | Portola Pharmaceuticals, Inc. | Inhibitors of protein kinases |
| MX2010011463A (en) | 2008-04-16 | 2011-06-03 | Portola Pharm Inc | 2, 6-diamino- pyrimidin- 5-yl-carboxamides as syk or jak kinases inhibitors. |
| US7829574B2 (en) | 2008-05-09 | 2010-11-09 | Hutchison Medipharma Enterprises Limited | Substituted quinazoline compounds and their use in treating angiogenesis-related diseases |
| SI2300013T1 (en) | 2008-05-21 | 2018-03-30 | Adriad Pharmacaceuticals, Inc. | Phosphorous derivatives as kinase inhibitors |
| US9273077B2 (en) | 2008-05-21 | 2016-03-01 | Ariad Pharmaceuticals, Inc. | Phosphorus derivatives as kinase inhibitors |
| US8445505B2 (en) | 2008-06-25 | 2013-05-21 | Irm Llc | Pyrimidine derivatives as kinase inhibitors |
| PE20100087A1 (en) | 2008-06-25 | 2010-02-08 | Irm Llc | COMPOUNDS AND COMPOSITIONS AS KINASE INHIBITORS |
| US8338439B2 (en) | 2008-06-27 | 2012-12-25 | Celgene Avilomics Research, Inc. | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
| US11351168B1 (en) | 2008-06-27 | 2022-06-07 | Celgene Car Llc | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
| DK2361248T3 (en) | 2008-06-27 | 2019-01-14 | Celgene Car Llc | Heteroberl compounds and uses thereof |
| US8426430B2 (en) | 2008-06-30 | 2013-04-23 | Hutchison Medipharma Enterprises Limited | Quinazoline derivatives |
| US7737157B2 (en) | 2008-08-29 | 2010-06-15 | Hutchison Medipharma Enterprises Limited | Pyrimidine compounds |
| US8809343B2 (en) | 2008-12-26 | 2014-08-19 | Fudan University | Pyrimidine derivative, preparation method and use thereof |
| PT2395983T (en) | 2009-02-13 | 2020-07-03 | Boehringer Ingelheim Int | Pharmaceutical composition comprising a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof |
| US20120189641A1 (en) | 2009-02-25 | 2012-07-26 | OSI Pharmaceuticals, LLC | Combination anti-cancer therapy |
| US8642834B2 (en) | 2009-02-27 | 2014-02-04 | OSI Pharmaceuticals, LLC | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
| EP2401613A2 (en) | 2009-02-27 | 2012-01-04 | OSI Pharmaceuticals, LLC | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
| WO2010099138A2 (en) | 2009-02-27 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
| ES2659725T3 (en) | 2009-05-05 | 2018-03-19 | Dana-Farber Cancer Institute, Inc. | EGFR inhibitors and disorder treatment procedure |
| US8933227B2 (en) | 2009-08-14 | 2015-01-13 | Boehringer Ingelheim International Gmbh | Selective synthesis of functionalized pyrimidines |
| US8729265B2 (en) | 2009-08-14 | 2014-05-20 | Boehringer Ingelheim International Gmbh | Regioselective preparation of 2-amino-5-trifluoromethylpyrimidine derivatives |
| CN102574829B (en) | 2009-09-30 | 2015-07-01 | 贝林格尔.英格海姆国际有限公司 | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
| EA020798B1 (en) | 2009-09-30 | 2015-01-30 | Бёрингер Ингельхайм Интернациональ Гмбх | Method for the preparation of a crystalline form of 1-chloro-4-(beta-d-glucopyranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)benzyl]benzene |
| UY32919A (en) | 2009-10-02 | 2011-04-29 | Boehringer Ingelheim Int | Pharmaceutical composition, pharmaceutical dosage form, procedure for its preparation, methods for its treatment and its uses |
| EP2516434B1 (en) * | 2009-12-23 | 2015-05-27 | Takeda Pharmaceutical Company Limited | Fused heteroaromatic pyrrolidinones as syk inhibitors |
| EP2552211A4 (en) * | 2010-03-26 | 2013-10-23 | Glaxo Group Ltd | Indazolyl-pyrimidines as kinase inhibitors |
| US8748423B2 (en) | 2010-04-16 | 2014-06-10 | Kinex Pharmaceuticals, Llc | Compositions and methods for the prevention and treatment of cancer |
| CN103154246B (en) | 2010-05-14 | 2015-11-25 | 达那-法伯癌症研究所 | Be used for the treatment of leukemic composition and method |
| CN103180318B (en) | 2010-05-14 | 2017-05-10 | 达那-法伯癌症研究所 | male contraceptive compositions and methods of use |
| BR122014024883A2 (en) | 2010-05-14 | 2019-08-20 | Dana-Farber Cancer Institute, Inc. | COMPOUNDS IN NEOPLASIA TREATMENT |
| EP3144298A1 (en) | 2010-08-10 | 2017-03-22 | Celgene Avilomics Research, Inc. | Besylate salt of a btk inhibitor |
| JP5956999B2 (en) | 2010-11-01 | 2016-07-27 | セルジーン アヴィロミクス リサーチ， インコーポレイテッド | Heteroaryl compounds and uses thereof |
| MX2013004894A (en) | 2010-11-01 | 2013-10-17 | Celgene Avilomics Res Inc | Heterocyclic compounds and uses thereof. |
| CA2816957A1 (en) | 2010-11-07 | 2012-05-10 | Targegen, Inc. | Compositions and methods for treating myelofibrosis |
| US8796255B2 (en) | 2010-11-10 | 2014-08-05 | Celgene Avilomics Research, Inc | Mutant-selective EGFR inhibitors and uses thereof |
| MY177742A (en) | 2010-12-17 | 2020-09-23 | Novartis Ag | Crystalline forms of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl-n4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
| EP2489663A1 (en) | 2011-02-16 | 2012-08-22 | Almirall, S.A. | Compounds as syk kinase inhibitors |
| US9174946B2 (en) | 2011-02-17 | 2015-11-03 | Cancer Therapeutics Crc Pty Ltd | Selective FAK inhibitors |
| JP5937111B2 (en) | 2011-02-17 | 2016-06-22 | カンサー・セラピューティクス・シーアールシー・プロプライエタリー・リミテッドＣａｎｃｅｒ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｃｒｃ Ｐｔｙ Ｌｉｍｉｔｅｄ | FAK inhibitor |
| UY33937A (en) | 2011-03-07 | 2012-09-28 | Boehringer Ingelheim Int | PHARMACEUTICAL COMPOSITIONS CONTAINING DPP-4 AND / OR SGLT-2 AND METFORMIN INHIBITORS |
| US9249124B2 (en) * | 2011-03-30 | 2016-02-02 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Aurora kinase inhibitors and methods of making and using thereof |
| HUE046988T2 (en) * | 2011-04-01 | 2020-04-28 | Univ Utah Res Found | Substituted n-phenylpyrimidin-2-amine analogs as inhibitors of the axl kinase |
| JP6027095B2 (en) | 2011-04-22 | 2016-11-16 | シグナル ファーマシューティカルズ，エルエルシー | Substituted diaminocarboxamides and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment using the same |
| WO2012149014A1 (en) | 2011-04-25 | 2012-11-01 | OSI Pharmaceuticals, LLC | Use of emt gene signatures in cancer drug discovery, diagnostics, and treatment |
| JP5999177B2 (en) | 2011-05-04 | 2016-09-28 | アリアド・ファーマシューティカルズ・インコーポレイテッド | Compound for inhibiting cell proliferation of EGFR-activated cancer |
| MX2013013090A (en) | 2011-05-10 | 2013-12-16 | Merck Sharp & Dohme | Aminopyrimidines as syk inhibitors. |
| EP2706852B1 (en) | 2011-05-10 | 2018-08-22 | Merck Sharp & Dohme Corp. | Bipyridylaminopyridines as syk inhibitors |
| EP2707357B1 (en) | 2011-05-10 | 2017-01-18 | Merck Sharp & Dohme Corp. | Pyridyl aminopyridines as syk inhibitors |
| US9006444B2 (en) | 2011-10-05 | 2015-04-14 | Merck Sharp & Dohme Corp. | Phenyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors |
| EP2763976B1 (en) | 2011-10-05 | 2016-05-18 | Merck Sharp & Dohme Corp. | 2-pyridyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors |
| WO2013052393A1 (en) | 2011-10-05 | 2013-04-11 | Merck Sharp & Dohme Corp. | 3-PYRIDYL CARBOXAMIDE-CONTAINING SPLEEN TYROSINE KINASE (Syk) INHIBITORS |
| AR088570A1 (en) | 2011-10-28 | 2014-06-18 | Celgene Avilomics Res Inc | METHODS TO TREAT AN ILLNESS OR DISORDER RELATED TO BRUTON TYROSINE KINASE |
| KR101401664B1 (en) * | 2011-11-15 | 2014-06-11 | 중앙대학교 산학협력단 | Novel pyrimidine-2,4-diamine derivatives for differentiation of neural stem cells and medical use thereof |
| AU2012340555B2 (en) | 2011-11-23 | 2016-10-20 | Portola Pharmaceuticals, Inc. | Pyrazine kinase inhibitors |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| JP6317319B2 (en) | 2012-03-15 | 2018-04-25 | セルジーン シーエーアール エルエルシー | Solid forms of epidermal growth factor receptor kinase inhibitors |
| MX356179B (en) | 2012-03-15 | 2018-05-17 | Celgene Avilomics Res Inc | Salts of an epidermal growth factor receptor kinase inhibitor. |
| US9192617B2 (en) | 2012-03-20 | 2015-11-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| WO2013152252A1 (en) | 2012-04-06 | 2013-10-10 | OSI Pharmaceuticals, LLC | Combination anti-cancer therapy |
| JP6469567B2 (en) | 2012-05-05 | 2019-02-13 | アリアド・ファーマシューティカルズ・インコーポレイテッド | Compound for inhibiting cell proliferation of EGFR-activated cancer |
| WO2013192125A1 (en) | 2012-06-20 | 2013-12-27 | Merck Sharp & Dohme Corp. | Pyrazolyl derivatives as syk inhibitors |
| US9487504B2 (en) | 2012-06-20 | 2016-11-08 | Merck Sharp & Dohme Corp. | Imidazolyl analogs as syk inhibitors |
| EP2863916B1 (en) | 2012-06-22 | 2018-07-18 | Merck Sharp & Dohme Corp. | Substituted pyridine spleen tyrosine kinase (syk) inhibitors |
| US9416111B2 (en) | 2012-06-22 | 2016-08-16 | Merck Sharp & Dohme Corp. | Substituted diazine and triazine spleen tyrosine kinease (Syk) inhibitors |
| WO2014031438A2 (en) | 2012-08-20 | 2014-02-27 | Merck Sharp & Dohme Corp. | SUBSTITUTED PHENYL SPLEEN TYROSINE KINASE (Syk) INHIBITORS |
| SI2890680T1 (en) | 2012-08-30 | 2018-08-31 | Athenex, Inc. Conventus Building | N-(3-fluorobenzyl)-2-(5-(4-morpholinophenyl)pyridin-2-yl) acetamide as protein tyrosine kinase modulators |
| WO2014048065A1 (en) | 2012-09-28 | 2014-04-03 | Merck Sharp & Dohme Corp. | Triazolyl derivatives as syk inhibitors |
| CN103864764A (en) * | 2012-12-11 | 2014-06-18 | 齐鲁制药有限公司 | Indazole-substituted pyrimidinamine derivative, and preparation method and use thereof |
| US9624210B2 (en) | 2012-12-12 | 2017-04-18 | Merck Sharp & Dohme Corp. | Amino-pyrimidine-containing spleen tyrosine kinase (Syk) inhibitors |
| EP2935226A4 (en) | 2012-12-21 | 2016-11-02 | Celgene Avilomics Res Inc | Heteroaryl compounds and uses thereof |
| US9598405B2 (en) | 2012-12-21 | 2017-03-21 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminopyridines as spleen tyrosine kinase inhibitors |
| CN105188371A (en) | 2013-02-08 | 2015-12-23 | 西建阿维拉米斯研究公司 | Erk inhibitors and uses thereof |
| WO2014159392A1 (en) | 2013-03-14 | 2014-10-02 | Dana-Farber Cancer Institute, Inc. | Bromodomain binding reagents and uses thereof |
| KR102334260B1 (en) | 2013-03-14 | 2021-12-02 | 스미토모 다이니폰 파마 온콜로지, 인크. | Jak2 and alk2 inhibitors and methods for their use |
| US20140303097A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| HUE041709T2 (en) | 2013-04-05 | 2019-05-28 | Boehringer Ingelheim Int | Therapeutic uses of empagliflozin |
| US11813275B2 (en) | 2013-04-05 | 2023-11-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US9611283B1 (en) | 2013-04-10 | 2017-04-04 | Ariad Pharmaceuticals, Inc. | Methods for inhibiting cell proliferation in ALK-driven cancers |
| LT2986304T (en) | 2013-04-18 | 2022-03-10 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US9745295B2 (en) | 2013-04-26 | 2017-08-29 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors |
| WO2014176216A1 (en) | 2013-04-26 | 2014-10-30 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminopyrimidines as spleen tyrosine kinase inhibitors |
| EP3024327B1 (en) | 2013-07-25 | 2019-09-04 | Dana-Farber Cancer Institute, Inc. | Inhibitors of transcription factors and uses thereof |
| US9492471B2 (en) | 2013-08-27 | 2016-11-15 | Celgene Avilomics Research, Inc. | Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase |
| US11446309B2 (en) | 2013-11-08 | 2022-09-20 | Dana-Farber Cancer Institute, Inc. | Combination therapy for cancer using bromodomain and extra-terminal (BET) protein inhibitors |
| WO2015094997A1 (en) | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors |
| WO2015095444A1 (en) | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors |
| EP3083559B1 (en) | 2013-12-20 | 2021-03-10 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors |
| US9415049B2 (en) | 2013-12-20 | 2016-08-16 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
| NZ715903A (en) | 2014-01-30 | 2017-06-30 | Signal Pharm Llc | Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use |
| CA2936865A1 (en) | 2014-01-31 | 2015-08-06 | Dana-Farber Cancer Institute, Inc. | Diaminopyrimidine benzenesulfone derivatives and uses thereof |
| KR20160111036A (en) | 2014-01-31 | 2016-09-23 | 다나-파버 캔서 인스티튜트 인크. | Diazepane derivatives and uses thereof |
| US10793571B2 (en) | 2014-01-31 | 2020-10-06 | Dana-Farber Cancer Institute, Inc. | Uses of diazepane derivatives |
| JP2017506666A (en) | 2014-02-28 | 2017-03-09 | テンシャ セラピューティクス，インコーポレイテッド | Treatment of symptoms related to hyperinsulinemia |
| WO2015138273A1 (en) | 2014-03-13 | 2015-09-17 | Merck Sharp & Dohme Corp. | 2-pyrazine carboxamides as spleen tyrosine kinase inhibitors |
| CN106661005A (en) * | 2014-07-16 | 2017-05-10 | 诺沃根公司 | Functionalised and substituted indoles as anti-cancer agents |
| KR20170032474A (en) | 2014-08-08 | 2017-03-22 | 다나-파버 캔서 인스티튜트 인크. | Dihydropteridinone derivatives and uses thereof |
| WO2016022902A1 (en) | 2014-08-08 | 2016-02-11 | Dana-Farber Cancer Institute, Inc. | Diazepane derivatives and uses thereof |
| ES2741785T3 (en) | 2014-08-13 | 2020-02-12 | Celgene Car Llc | Forms and compositions of an ERK inhibitor |
| US10266549B2 (en) * | 2014-08-25 | 2019-04-23 | Salk Institute For Biological Studies | ULK1 inhibitors and methods using same |
| CA2965330A1 (en) | 2014-10-27 | 2016-05-06 | Tensha Therapeutics, Inc. | Bromodomain inhibitors |
| NZ732793A (en) | 2014-12-16 | 2023-07-28 | Signal Pharm Llc | Formulations of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methycyclohexylamino)-pyrimidine-5-carboxamide |
| ES2882954T3 (en) | 2014-12-16 | 2021-12-03 | Signal Pharm Llc | Medical uses comprising methods for the measurement of inhibition of c-Jun N-terminal kinase in the skin |
| EP3250557A4 (en) | 2015-01-29 | 2018-06-20 | Signal Pharmaceuticals, LLC | Isotopologues of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide |
| US10702527B2 (en) | 2015-06-12 | 2020-07-07 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
| JP6805232B2 (en) | 2015-07-24 | 2020-12-23 | セルジーン コーポレイション | Methods for Synthesizing (1R, 2R, 5R) -5-Amino-2-methylcyclohexanol Hydrochloride and Intermediates Useful |
| PE20181086A1 (en) | 2015-09-11 | 2018-07-05 | Dana Farber Cancer Inst Inc | ACETAMIDE HAVE THRIZOLODIAZEPINES AND USES OF THE SAME |
| BR112018004618A2 (en) | 2015-09-11 | 2018-09-25 | Dana-Farber Cancer Institute, Inc. | cyan thienotriazoldiazepines and uses thereof |
| BR112018009798A8 (en) | 2015-11-25 | 2019-02-26 | Dana Farber Cancer Inst Inc | bivalent bromodomain inhibitors and their uses |
| CN112739345A (en) | 2017-11-06 | 2021-04-30 | 斯奈普生物公司 | PIM kinase inhibitor compositions, methods and uses thereof |
| BR112020020246A8 (en) | 2018-04-05 | 2022-10-18 | Sumitomo Dainippon Pharma Oncology Inc | AXL KINASE INHIBITORS AND THEIR USE |
| KR20210038906A (en) | 2018-07-26 | 2021-04-08 | 스미토모 다이니폰 파마 온콜로지, 인크. | Methods of treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use therein |
| CN111072571B (en) * | 2018-10-18 | 2021-05-14 | 北京西博医药研究有限公司 | Dithiocarbamates as FAK inhibitors |
| CN111171017B (en) * | 2018-11-09 | 2021-12-24 | 天津大学 | Pyrimidine-based derivatives, their preparation and use |
| CN111362922A (en) * | 2018-12-26 | 2020-07-03 | 上海喆邺生物科技有限公司 | 2, 4-diaminopyrimidine derivatives and their use |
| KR20210143803A (en) * | 2019-03-15 | 2021-11-29 | 더 제너럴 하스피탈 코포레이션 | Novel small molecule inhibitors of TEAD transcription factors |
| WO2020253862A1 (en) * | 2019-06-21 | 2020-12-24 | 上海翰森生物医药科技有限公司 | Nitrogen-containing aryl phosphorus oxide derivative, preparation method therefor and use thereof |
| CN111484484B (en) * | 2020-04-13 | 2021-11-23 | 沈阳药科大学 | 2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof |
| CN112390760B (en) * | 2020-10-15 | 2022-07-29 | 北京师范大学 | FAK-targeting compound and preparation method and application thereof |
| CN114230524A (en) * | 2021-12-28 | 2022-03-25 | 南通大学 | (5-fluoro-2-anilinopyrimidin-4-yl) amino-N-hydroxybenzamide derivative and preparation method and application thereof |
| CN114031559A (en) * | 2021-12-28 | 2022-02-11 | 南通大学 | Aryl nitrogen-containing heterocycle modified 5-fluoro-pyrimidinediamine benzoate and preparation method and application thereof |
Family Cites Families (80)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL129020C (en) | 1964-12-15 | |||
| US3432493A (en) | 1966-06-27 | 1969-03-11 | Abbott Lab | Substituted sulfanilamides |
| GB1524747A (en) | 1976-05-11 | 1978-09-13 | Ici Ltd | Polypeptide |
| ATE28864T1 (en) | 1982-07-23 | 1987-08-15 | Ici Plc | AMIDE DERIVATIVES. |
| IL86632A0 (en) | 1987-06-15 | 1988-11-30 | Ciba Geigy Ag | Derivatives substituted at methyl-amino nitrogen |
| NZ243082A (en) | 1991-06-28 | 1995-02-24 | Ici Plc | 4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof |
| GB9300059D0 (en) | 1992-01-20 | 1993-03-03 | Zeneca Ltd | Quinazoline derivatives |
| TW225528B (en) | 1992-04-03 | 1994-06-21 | Ciba Geigy Ag | |
| ATE348110T1 (en) | 1992-10-28 | 2007-01-15 | Genentech Inc | HVEGF RECEPTOR AS A VEGF ANTAGONIST |
| GB9325217D0 (en) | 1993-12-09 | 1994-02-09 | Zeneca Ltd | Pyrimidine derivatives |
| WO1996010028A1 (en) | 1994-09-29 | 1996-04-04 | Novartis Ag | PYRROLO[2,3-d]PYRIMIDINES AND THEIR USE |
| EP0813525B9 (en) | 1995-03-10 | 2004-02-04 | Berlex Laboratories, Inc. | Benzamidine derivatives their preparation and their use as anti-coagulants |
| GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
| US5880141A (en) | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
| BR9609617B1 (en) | 1995-07-06 | 2010-07-27 | 7h-pyrrol [2,3-d] pyrimidine derivatives, and pharmaceutical composition. | |
| GB9517060D0 (en) | 1995-08-17 | 1995-10-25 | Ciba Geigy Ag | Acylated oligopeptide derivatives |
| GB9516842D0 (en) | 1995-08-17 | 1995-10-18 | Ciba Geigy Ag | Various acylated oligopeptides |
| GB9523675D0 (en) * | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
| CH690773A5 (en) | 1996-02-01 | 2001-01-15 | Novartis Ag | Pyrrolo (2,3-d) pyrimides and their use. |
| US5760041A (en) | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
| GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
| WO1997032879A1 (en) | 1996-03-06 | 1997-09-12 | Novartis Ag | 7-ALKYL-PYRROLO[2,3-d]PYRIMIDINES |
| BR9708640B1 (en) | 1996-04-12 | 2013-06-11 | irreversible tyrosine kinase inhibitors and pharmaceutical composition comprising them. | |
| EP0907642B1 (en) | 1996-06-24 | 2005-11-02 | Pfizer Inc. | Phenylamino-substituted tricyclic derivatives for treatment of hyperproliferative diseases |
| WO1997049706A1 (en) | 1996-06-25 | 1997-12-31 | Novartis Ag | SUBSTITUTED 7-AMINO-PYRROLO[3,2-d]PYRIMIDINES AND THE USE THEREOF |
| DE19638745C2 (en) | 1996-09-11 | 2001-05-10 | Schering Ag | Monoclonal antibodies against the extracellular domain of the human VEGF receptor protein (KDR) |
| CN1234798A (en) | 1996-09-12 | 1999-11-10 | 舍林股份公司 | Benzamidine derivatives substituted by cyclic amino acid or cyclic hydroxy acid derivatives and their use as anti-coagulants |
| AU4342997A (en) | 1996-09-13 | 1998-04-02 | Sugen, Inc. | Use of quinazoline derivatives for the manufacture of a medicament in the reatment of hyperproliferative skin disorders |
| GB9619284D0 (en) | 1996-09-16 | 1996-10-30 | Celltech Therapeutics Ltd | Chemical compounds |
| US6004985A (en) | 1996-10-09 | 1999-12-21 | Berlex Laboratories, Inc. | Thio acid derived monocylic N-heterocyclics as anticoagulants |
| EP0837063A1 (en) | 1996-10-17 | 1998-04-22 | Pfizer Inc. | 4-Aminoquinazoline derivatives |
| GB9622363D0 (en) | 1996-10-28 | 1997-01-08 | Celltech Therapeutics Ltd | Chemical compounds |
| CO4950519A1 (en) | 1997-02-13 | 2000-09-01 | Novartis Ag | PHTHALAZINES, PHARMACEUTICAL PREPARATIONS THAT UNDERSTAND THEM AND THE PROCESS FOR THEIR PREPARATION |
| GB9705361D0 (en) | 1997-03-14 | 1997-04-30 | Celltech Therapeutics Ltd | Chemical compounds |
| CO4940418A1 (en) | 1997-07-18 | 2000-07-24 | Novartis Ag | MODIFICATION OF A CRYSTAL OF A DERIVATIVE OF N-PHENYL-2-PIRIMIDINAMINE, PROCESSES FOR ITS MANUFACTURE AND USE |
| GB9721069D0 (en) | 1997-10-03 | 1997-12-03 | Pharmacia & Upjohn Spa | Polymeric derivatives of camptothecin |
| US6432963B1 (en) * | 1997-12-15 | 2002-08-13 | Yamanouchi Pharmaceutical Co., Ltd. | Pyrimidine-5-carboxamide derivatives |
| EP0945443B9 (en) | 1998-03-27 | 2003-08-13 | Janssen Pharmaceutica N.V. | HIV inhibiting pyrimidine derivatives |
| ES2342240T3 (en) | 1998-08-11 | 2010-07-02 | Novartis Ag | ISOQUINOLINE DERIVATIVES WITH ACTIVITY INHIBITED BY ANGIOGENIA. |
| WO2000012485A1 (en) | 1998-08-29 | 2000-03-09 | Astrazeneca Ab | Pyrimidine compounds |
| GB9824579D0 (en) | 1998-11-10 | 1999-01-06 | Novartis Ag | Organic compounds |
| PL204427B1 (en) | 1998-11-10 | 2010-01-29 | Janssen Pharmaceutica Nv | Hiv replication inhibiting pyrimidines |
| UA71587C2 (en) | 1998-11-10 | 2004-12-15 | Шерінг Акцієнгезелльшафт | Anthranilic acid amides and use thereof as medicaments |
| US6262088B1 (en) | 1998-11-19 | 2001-07-17 | Berlex Laboratories, Inc. | Polyhydroxylated monocyclic N-heterocyclic derivatives as anti-coagulants |
| US6127376A (en) | 1998-12-04 | 2000-10-03 | Berlex Laboratories, Inc. | Aryl and heterocyclyl substituted pyrimidine derivatives as anti-coagulants |
| ATE300957T1 (en) | 1998-12-22 | 2005-08-15 | Genentech Inc | ANTAGONISTS OF VASCULAR-ENDOTHELIAL CELL GROWTH FACTORS AND THEIR APPLICATION |
| GB9828511D0 (en) | 1998-12-24 | 1999-02-17 | Zeneca Ltd | Chemical compounds |
| GB9903547D0 (en) | 1999-02-16 | 1999-04-07 | Novartis Ag | Organic compounds |
| CN1221262C (en) | 1999-03-30 | 2005-10-05 | 诺瓦提斯公司 | Phthalazine derivatives for treating inflammatory diseases |
| US6797706B1 (en) | 1999-06-09 | 2004-09-28 | Yamanouchi Pharmaceutical Co., Ltd. | Heterocyclecarboxamide derivative |
| GB9914258D0 (en) | 1999-06-18 | 1999-08-18 | Celltech Therapeutics Ltd | Chemical compounds |
| WO2001025220A1 (en) | 1999-10-07 | 2001-04-12 | Amgen Inc. | Triazine kinase inhibitors |
| GB9924092D0 (en) | 1999-10-13 | 1999-12-15 | Zeneca Ltd | Pyrimidine derivatives |
| GB9924862D0 (en) | 1999-10-20 | 1999-12-22 | Celltech Therapeutics Ltd | Chemical compounds |
| EP1230225A2 (en) | 1999-11-01 | 2002-08-14 | Eli Lilly And Company | Pharmaceutically active 4-substituted pyrimidine derivatives |
| AU2457201A (en) | 1999-12-28 | 2001-07-09 | Bristol-Myers Squibb Company | Cytokine, especially tnf-alpha, inhibitors |
| GB0001930D0 (en) | 2000-01-27 | 2000-03-22 | Novartis Ag | Organic compounds |
| ATE295365T1 (en) | 2000-02-09 | 2005-05-15 | Novartis Pharma Gmbh | PYRIDINE DERIVATIVES AS ANGIOGENESIS AND/OR VEGF RECEPTOR TYROSINE KINASE INHIBITORS |
| HUP0301117A3 (en) * | 2000-02-17 | 2004-01-28 | Amgen Inc Thousand Oaks | Imidazole derivatives kinase inhibitors, their use, process for their preparation and pharmaceutical compositions containing them |
| AU780527B2 (en) | 2000-02-25 | 2005-03-24 | F. Hoffmann-La Roche Ag | Adenosine receptor modulators |
| GB0004890D0 (en) * | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
| GB0004887D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
| GB0004888D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
| US6316722B1 (en) | 2000-03-01 | 2001-11-13 | Marconi Communications, Inc. | Vented pedestal for electronics housing |
| GB0019632D0 (en) | 2000-08-09 | 2000-09-27 | Novartis Ag | Organic compounds |
| US20020132823A1 (en) | 2001-01-17 | 2002-09-19 | Jiahuai Han | Assay method |
| US6939874B2 (en) * | 2001-08-22 | 2005-09-06 | Amgen Inc. | Substituted pyrimidinyl derivatives and methods of use |
| WO2003030909A1 (en) | 2001-09-25 | 2003-04-17 | Bayer Pharmaceuticals Corporation | 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer |
| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| CA2476281A1 (en) | 2002-02-08 | 2003-08-14 | Smithkline Beecham Corporation | Pyrimidine compounds |
| GB0206215D0 (en) * | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
| AU2003231231A1 (en) | 2002-05-06 | 2003-11-11 | Bayer Pharmaceuticals Corporation | Pyridinyl amino pyrimidine derivatives useful for treating hyper-proliferative disorders |
| ES2373226T3 (en) | 2002-06-28 | 2012-02-01 | Astellas Pharma Inc. | DERIVATIVE OF DIAMINOPIRIMIDINCARBOXAMIDA. |
| UA80767C2 (en) | 2002-12-20 | 2007-10-25 | Pfizer Prod Inc | Pyrimidine derivatives for the treatment of abnormal cell growth |
| US7514446B2 (en) * | 2003-02-20 | 2009-04-07 | Smithkline Beecham Corporation | Pyrimidine compounds |
| GB0305929D0 (en) | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
| NZ585188A (en) | 2003-08-15 | 2011-09-30 | Novartis Ag | 2,4-Pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
| GB0321710D0 (en) | 2003-09-16 | 2003-10-15 | Novartis Ag | Organic compounds |
| WO2005026130A1 (en) | 2003-09-18 | 2005-03-24 | Novartis Ag | 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders |
| US7557207B2 (en) | 2004-11-24 | 2009-07-07 | Rigel Pharmaceuticals, Inc. | Spiro 2,4-pyrimidinediamine compounds and their uses |
-
2002
- 2002-03-15 GB GBGB0206215.6A patent/GB0206215D0/en not_active Ceased
-
2003
- 2003-03-14 CN CNA038061015A patent/CN1697830A/en active Pending
- 2003-03-14 CN CN2011102019723A patent/CN102336716A/en active Pending
- 2003-03-14 SI SI200332226T patent/SI2308855T1/en unknown
- 2003-03-14 EP EP03744366A patent/EP1487805B1/en not_active Expired - Lifetime
- 2003-03-14 AU AU2003227070A patent/AU2003227070B2/en not_active Ceased
- 2003-03-14 DK DK03744366.0T patent/DK1487805T3/en active
- 2003-03-14 CA CA2479133A patent/CA2479133C/en not_active Expired - Fee Related
- 2003-03-14 US US10/507,060 patent/US7943627B2/en active Active
- 2003-03-14 IL IL16381703A patent/IL163817A0/en unknown
- 2003-03-14 PT PT03744366T patent/PT1487805E/en unknown
- 2003-03-14 JP JP2003576410A patent/JP4362377B2/en not_active Expired - Lifetime
- 2003-03-14 PL PL03370834A patent/PL370834A1/en not_active Application Discontinuation
- 2003-03-14 MX MXPA04009058A patent/MXPA04009058A/en active IP Right Grant
- 2003-03-14 KR KR1020047013748A patent/KR100618037B1/en not_active IP Right Cessation
- 2003-03-14 ES ES03744366T patent/ES2387270T3/en not_active Expired - Lifetime
- 2003-03-14 EP EP10163904A patent/EP2308855B1/en not_active Expired - Lifetime
- 2003-03-14 CN CN2010101974578A patent/CN101830889B/en not_active Expired - Lifetime
- 2003-03-14 ES ES10163904T patent/ES2394616T3/en not_active Expired - Lifetime
- 2003-03-14 BR BR0308461-2A patent/BR0308461A/en not_active IP Right Cessation
- 2003-03-14 PT PT101639045T patent/PT2308855E/en unknown
- 2003-03-14 NZ NZ535109A patent/NZ535109A/en unknown
- 2003-03-14 SI SI200332183T patent/SI1487805T1/en unknown
- 2003-03-14 WO PCT/EP2003/002710 patent/WO2003078404A1/en active IP Right Grant
- 2003-03-14 RU RU2004130488/04A patent/RU2324684C2/en not_active IP Right Cessation
- 2003-03-14 DK DK10163904.5T patent/DK2308855T3/en active
- 2003-03-14 PL PL395232A patent/PL395232A1/en unknown
-
2004
- 2004-08-24 ZA ZA200406709A patent/ZA200406709B/en unknown
- 2004-08-30 IL IL163817A patent/IL163817A/en not_active IP Right Cessation
- 2004-09-13 EC EC2004005294A patent/ECSP045294A/en unknown
- 2004-09-30 CO CO04097772A patent/CO5640117A2/en not_active Application Discontinuation
- 2004-10-14 NO NO20044374A patent/NO20044374L/en unknown
-
2011
- 2011-03-23 US US13/069,816 patent/US8431589B2/en not_active Expired - Lifetime
- 2011-05-31 HK HK11105431.3A patent/HK1151292A1/xx not_active IP Right Cessation
-
2012
- 2012-09-13 CY CY20121100842T patent/CY1113118T1/en unknown
- 2012-12-19 CY CY20121101237T patent/CY1113508T1/en unknown
-
2013
- 2013-03-15 US US13/837,137 patent/US20130345180A1/en not_active Abandoned
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101830889B (en) | Pyrimidine derivatives | |
| CN100584832C (en) | 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders | |
| CN1882578B (en) | 2,4 di (hetero) -arylamino-pyrimidine derivatives as zap-70 and/or syk inhibitors | |
| DE60003001T2 (en) | pyrimidine | |
| CN102131788B (en) | Compounds and compositions as protein kinase inhibitors | |
| KR100928602B1 (en) | Cyclic diaryl urea suitable as a tyrosine kinase inhibitor | |
| MXPA02009255A (en) | 4 amino 5 cyano 2 anilino pyrimidine derivatives and their use as inhibitors of cell cycle kinases. | |
| JP2003525277A (en) | Pyrimidine compounds | |
| TW200804364A (en) | New compounds | |
| JP2004502763A (en) | Pyrimidine derivatives | |
| KR20060124722A (en) | Isothiourea derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: NOVARTIS CO., LTD. Free format text: FORMER NAME: NOVARTIS AG |
|
| CP01 | Change in the name or title of a patent holder |
Address after: Basel, Switzerland Patentee after: NOVARTIS AG Address before: Basel, Switzerland Patentee before: Novartis AG |
|
| CX01 | Expiry of patent term |
Granted publication date: 20130102 |
|
| CX01 | Expiry of patent term |